Noninvasive molecular analysis of Helicobacter pylori : Is it time for tailored first-line therapy?
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摘要
The main problem of Helicobacter pylori(H. pylori) infection management is linked to antibiotic resistances. This phenomenon has grown in the last decade, inducing a dramatic decline in conventional regimen effectiveness. The causes of resistance are point mutations in bacterial DNA, which interfere with antibiotic mechanism of action, especially clarithromycin and levofloxacin. Therefore, international guidelines have recently discouraged their use in areas with a relevant resistance percentage, suggesting first-line schedules with expected high eradication rates, i.e., bismuth containing or non-bismuth quadruple therapies. These regimens require the daily assumption of a large number of tablets. Consequently, a complete adherence is expected only in subjects who may be motivated by the presence of major disorders. However, an incomplete adherence to antibiotic therapies may lead to resistance onset, since sub-inhibitory concentrations could stimulate the selection of resistant mutants. Of note, a recent meta-analysis suggests that susceptibility tests may be more useful for the choice of first than second-line or rescue treatment. Additionally, susceptibility guided therapy has been demonstrated to be highly effective and superior to empiric treatments by both meta-analyses and recent clinical studies. Conventional susceptibility test is represented by culture and antibiogram. However, the method is not available everywhere mainly for methodology-related factors and fails to detect hetero-resistances. Polymerase chain reaction(PCR)-based, culture-free techniques on gastric biopsy samples are accurate in finding even minimal traces of genotypic resistant strains and hetero-resistant status by the identification of specific point mutations. The need for an invasive endoscopic procedure has been the most important limit to their spread. A further step has, moreover, been the detection of point mutations in bacterial DNA fecal samples. Few studies on clarithromycin susceptibility have shown an overall high sensitivity and specificity when compared with culture or PCR on gastric biopsies. On these bases, two commercial tests are now available although they have shown some controversial findings. A novel PCR method showed a full concordance between tissue and stool results in a preliminary experience. In conclusion, despite poor validation, there is increasing evidence of a potential availability of noninvasive investigations able to detect H. pylori resistances to antibiotics. These kinds of analysis are currently at a very early phase of development and caution should be paid about their clinical application. Only further studies aimed to evaluate their sensitivity and specificity will afford novel data for solid considerations. Nevertheless, noninvasive molecular tests may improve patient compliance, time/cost of infection management and therapeutic outcome. Moreover, the potential risk of a future increase of resistance to quadruple regimens as a consequence of their use on large scale and incomplete patient adherence could be avoided.
The main problem of Helicobacter pylori(H. pylori) infection management is linked to antibiotic resistances. This phenomenon has grown in the last decade, inducing a dramatic decline in conventional regimen effectiveness. The causes of resistance are point mutations in bacterial DNA, which interfere with antibiotic mechanism of action, especially clarithromycin and levofloxacin. Therefore, international guidelines have recently discouraged their use in areas with a relevant resistance percentage, suggesting first-line schedules with expected high eradication rates, i.e., bismuth containing or non-bismuth quadruple therapies. These regimens require the daily assumption of a large number of tablets. Consequently, a complete adherence is expected only in subjects who may be motivated by the presence of major disorders. However, an incomplete adherence to antibiotic therapies may lead to resistance onset, since sub-inhibitory concentrations could stimulate the selection of resistant mutants. Of note, a recent meta-analysis suggests that susceptibility tests may be more useful for the choice of first than second-line or rescue treatment. Additionally, susceptibility guided therapy has been demonstrated to be highly effective and superior to empiric treatments by both meta-analyses and recent clinical studies. Conventional susceptibility test is represented by culture and antibiogram. However, the method is not available everywhere mainly for methodology-related factors and fails to detect hetero-resistances. Polymerase chain reaction(PCR)-based, culture-free techniques on gastric biopsy samples are accurate in finding even minimal traces of genotypic resistant strains and hetero-resistant status by the identification of specific point mutations. The need for an invasive endoscopic procedure has been the most important limit to their spread. A further step has, moreover, been the detection of point mutations in bacterial DNA fecal samples. Few studies on clarithromycin susceptibility have shown an overall high sensitivity and specificity when compared with culture or PCR on gastric biopsies. On these bases, two commercial tests are now available although they have shown some controversial findings. A novel PCR method showed a full concordance between tissue and stool results in a preliminary experience. In conclusion, despite poor validation, there is increasing evidence of a potential availability of noninvasive investigations able to detect H. pylori resistances to antibiotics. These kinds of analysis are currently at a very early phase of development and caution should be paid about their clinical application. Only further studies aimed to evaluate their sensitivity and specificity will afford novel data for solid considerations. Nevertheless, noninvasive molecular tests may improve patient compliance, time/cost of infection management and therapeutic outcome. Moreover, the potential risk of a future increase of resistance to quadruple regimens as a consequence of their use on large scale and incomplete patient adherence could be avoided.
The main problem of Helicobacter pylori(H. pylori) infection management is linked to antibiotic resistances. This phenomenon has grown in the last decade, inducing a dramatic decline in conventional regimen effectiveness. The causes of resistance are point mutations in bacterial DNA, which interfere with antibiotic mechanism of action, especially clarithromycin and levofloxacin. Therefore, international guidelines have recently discouraged their use in areas with a relevant resistance percentage, suggesting first-line schedules with expected high eradication rates, i.e., bismuth containing or non-bismuth quadruple therapies. These regimens require the daily assumption of a large number of tablets. Consequently, a complete adherence is expected only in subjects who may be motivated by the presence of major disorders. However, an incomplete adherence to antibiotic therapies may lead to resistance onset, since sub-inhibitory concentrations could stimulate the selection of resistant mutants. Of note, a recent meta-analysis suggests that susceptibility tests may be more useful for the choice of first than second-line or rescue treatment. Additionally, susceptibility guided therapy has been demonstrated to be highly effective and superior to empiric treatments by both meta-analyses and recent clinical studies. Conventional susceptibility test is represented by culture and antibiogram. However, the method is not available everywhere mainly for methodology-related factors and fails to detect hetero-resistances. Polymerase chain reaction(PCR)-based, culture-free techniques on gastric biopsy samples are accurate in finding even minimal traces of genotypic resistant strains and hetero-resistant status by the identification of specific point mutations. The need for an invasive endoscopic procedure has been the most important limit to their spread. A further step has, moreover, been the detection of point mutations in bacterial DNA fecal samples. Few studies on clarithromycin susceptibility have shown an overall high sensitivity and specificity when compared with culture or PCR on gastric biopsies. On these bases, two commercial tests are now available although they have shown some controversial findings. A novel PCR method showed a full concordance between tissue and stool results in a preliminary experience. In conclusion, despite poor validation, there is increasing evidence of a potential availability of noninvasive investigations able to detect H. pylori resistances to antibiotics. These kinds of analysis are currently at a very early phase of development and caution should be paid about their clinical application. Only further studies aimed to evaluate their sensitivity and specificity will afford novel data for solid considerations. Nevertheless, noninvasive molecular tests may improve patient compliance, time/cost of infection management and therapeutic outcome. Moreover, the potential risk of a future increase of resistance to quadruple regimens as a consequence of their use on large scale and incomplete patient adherence could be avoided.
引文
1 Eusebi LH,Zagari RM,Bazzoli F.Epidemiology of Helicobacter pylori infection.Helicobacter 2014;19 Suppl 1:1-5[PMID:25167938 DOI:10.1111/hel.12165]
2 O’Connor A,Gisbert JP,O’Morain C,Ladas S.Treatment of Helicobacter pylori Infection 2015.Helicobacter 2015;20 Suppl 1:54-61[PMID:26372826 DOI:10.1111/hel.12258]
3 Ierardi E,Giorgio F,Losurdo G,Di Leo A,Principi M.How antibiotic resistances could change Helicobacter pylori treatment:Amatter of geography?World J Gastroenterol 2013;19:8168-8180[PMID:24363506 DOI:10.3748/wjg.v19.i45.8168]
4 Georgopoulos SD,Papastergiou V,Karatapanis S.Current options for the treatment of Helicobacter pylori.Expert Opin Pharmacother 2013;14:211-223[PMID:23331077 DOI:10.1517/14656566.2013.763926]
5 De Francesco V,Giorgio F,Hassan C,Manes G,Vannella L,Panella C,Ierardi E,Zullo A.Worldwide H.pylori antibiotic resistance:a systematic review.J Gastrointestin Liver Dis 2010;19:409-414[PMID:21188333]
6 Mégraud F.H pylori antibiotic resistance:prevalence,importance,and advances in testing.Gut 2004;53:1374-1384[PMID:15306603]
7 De Francesco V,Margiotta M,Zullo A,Hassan C,Troiani L,Burattini O,Stella F,Di Leo A,Russo F,Marangi S,Monno R,Stoppino V,Morini S,Panella C,Ierardi E.Clarithromycinresistant genotypes and eradication of Helicobacter pylori.Ann Intern Med 2006;144:94-100[PMID:16418408]
8 De Francesco V,Zullo A,Giorgio F,Saracino I,Zaccaro C,Hassan C,Ierardi E,Di Leo A,Fiorini G,Castelli V,Lo Re G,Vaira D.Change of point mutations in Helicobacter pylori r RNA associated with clarithromycin resistance in Italy.J Med Microbiol 2014;63:453-457[PMID:24344205 DOI:10.1099/jmm.0.067942-0]
9 Liou JM,Chang CY,Sheng WH,Wang YC,Chen MJ,Lee YC,Hung HW,Chian H,Chang SC,Wu MS,Lin JT.Genotypic resistance in Helicobacter pylori strains correlates with susceptibility test and treatment outcomes after levofloxacin-and clarithromycin-based therapies.Antimicrob Agents Chemother2011;55:1123-1129[PMID:21189342DOI:10.1128/AAC.01131-10]
10 Fallone CA,Chiba N,van Zanten SV,Fischbach L,Gisbert JP,Hunt RH,Jones NL,Render C,Leontiadis GI,Moayyedi P,Marshall JK.The Toronto Consensus for the Treatment of Helicobacter pylori Infection in Adults.Gastroenterology2016;151:51-69.e14[PMID:27102658DOI:10.1053/j.gastro.2016.04.006]
11 Malfertheiner P,Megraud F,O’Morain CA,Gisbert JP,Kuipers EJ,Axon AT,Bazzoli F,Gasbarrini A,Atherton J,Graham DY,Hunt R,Moayyedi P,Rokkas T,Rugge M,Selgrad M,Suerbaum S,Sugano K,El-Omar EM.Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report.Gut 2017;66:6-30[PMID:27707777 DOI:10.1136/gutjnl-2016-312288]
12 Fock KM,Katelaris P,Sugano K,Ang TL,Hunt R,Talley NJ,Lam SK,Xiao SD,Tan HJ,Wu CY,Jung HC,Hoang BH,Kachintorn U,Goh KL,Chiba T,Rani AA.Second Asia-Pacific Consensus Guidelines for Helicobacter pylori infection.J Gastroenterol Hepatol 2009;24:1587-1600[PMID:19788600 DOI:10.1111/j.1440-1746.2009.05982.x]
13 Lee M,Kemp JA,Canning A,Egan C,Tataronis G,Farraye FA.A randomized controlled trial of an enhanced patient compliance program for Helicobacter pylori therapy.Arch Intern Med 1999;159:2312-2316
14 Zullo A,Hassan C,De Francesco V,Repici A,Manta R,Tomao S,Annibale B,Vaira D.Helicobacter pylori and functional dyspepsia:an unsolved issue?World J Gastroenterol 2014;20:8957-8963[PMID:25083068 DOI:10.3748/wjg.v20.i27.8957]
15 Megraud F,Coenen S,Versporten A,Kist M,Lopez-Brea M,Hirschl AM,Andersen LP,Goossens H,Glupczynski Y.Helicobacter pylori resistance to antibiotics in Europe and its relationship to antibiotic consumption.Gut 2013;62:34-42[PMID:22580412 DOI:10.1136/gutjnl-2012-302254]
16 Graham DY,Lee SY.How to Effectively Use Bismuth Quadruple Therapy:The Good,the Bad,and the Ugly.Gastroenterol Clin North Am 2015;44:537-563[PMID:26314667 DOI:10.1016/j.gtc.2015.05.003]
17 Graham DY,Lee YC,Wu MS.Rational Helicobacter pylori therapy:evidence-based medicine rather than medicine-based evidence.Clin Gastroenterol Hepatol 2014;12:177-186.e3;Discussion e12-3[PMID:23751282]
18 Losurdo G,Giorgio F,Iannone A,Principi M,Barone M,Di Leo A,Ierardi E.Role of concomitant therapy for Helicobacter pylori eradication:A technical note.World J Gastroenterol 2016;22:8638-8640[PMID:27784977 DOI:10.3748/wjg.v22.i38.8638]
19 Wenzhen Y,Yumin L,Quanlin G,Kehu Y,Lei J,Donghai W,Lijuan Y.Is antimicrobial susceptibility testing necessary before first-line treatment for Helicobacter pylori infection?Meta-analysis of randomized controlled trials.Intern Med 2010;49:1103-1109[PMID:20558925]
20 López-Góngora S,Puig I,Calvet X,Villoria A,Baylina M,Mu?oz N,Sanchez-Delgado J,Suarez D,García-Hernando V,Gisbert JP.Systematic review and meta-analysis:susceptibility-guided versus empirical antibiotic treatment for Helicobacter pylori infection.JAntimicrob Chemother 2015;70:2447-2455[PMID:26078393DOI:10.1093/jac/dkv155]
21 Ferenc S,Gnus J,Ko?cielna M,Kinda M,Yarka A,Stewart L,Witkiewicz W.High antibiotic resistance of Helicobacter pylori and its effect on tailored and empiric eradication of the organism in Lower Silesia,Poland.Helicobacter 2017;22:[PMID:27879042DOI:10.1111/hel.12365]
22 Zhou L,Zhang J,Song Z,He L,Li Y,Qian J,Bai P,Xue Y,Wang Y,Lin S.Tailored versus Triple plus Bismuth or Concomitant Therapy as Initial Helicobacter pylori Treatment:A Randomized Trial.Helicobacter 2016;21:91-99[PMID:26104022 DOI:10.1111/hel.12242]
23 Kj?ller M,Fischer A,Justesen T.Transport conditions and number of biopsies necessary for culture of Helicobacter pylori.Eur J Clin Microbiol Infect Dis 1991;10:166-167[PMID:2060517]
24 Monno R,Giorgio F,Carmine P,Soleo L,Cinquepalmi V,Ierardi E.Helicobacter pylori clarithromycin resistance detected by Etest and Taq Man real-time polymerase chain reaction:a comparative study.APMIS 2012;120:712-717[PMID:22882260 DOI:10.1111/j.1600-0463.2012.02896.x]
25 De Francesco V,Margiotta M,Zullo A,Hassan C,Valle ND,Burattini O,Cea U,Stoppino G,Amoruso A,Stella F,Morini S,Panella C,Ierardi E.Primary clarithromycin resistance in Italy assessed on Helicobacter pylori DNA sequences by Taq Man real-time polymerase chain reaction.Aliment Pharmacol Ther 2006;23:429-435[PMID:16423002 DOI:10.1111/j.1365-2036.2006.02769.x]
26 De Francesco V,Zullo A,Ierardi E,Giorgio F,Perna F,Hassan C,Morini S,Panella C,Vaira D.Phenotypic and genotypic Helicobacter pylori clarithromycin resistance and therapeutic outcome:benefits and limits.J Antimicrob Chemother 2010;65:327-332[PMID:20008044 DOI:10.1093/jac/dkp445]
27 Ierardi E,Giorgio F,Losurdo G,Sorrentino C,Principi M,Di Leo A.Detection of Helicobacter pylori DNA sequences in gastric biopsy samples to refine the diagnosis and therapy.J Med Microbiol 2015;64:788-789[PMID:25934547 DOI:10.1099/jmm.0.000075]
28 Notarnicola M,Russo F,Cavallini A,Bianco M,Jirillo E,Pece S,Leoci C,Di Matteo G,Di Leo A.PCR identification of Helicobacter pylori in faeces from patients with gastroduodenal pathology.Med Sci Res 1996;24:785-787
29 Gramley WA,Asghar A,Frierson HF,Powell SM.Detection of Helicobacter pylori DNA in fecal samples from infected individuals.J Clin Microbiol 1999;37:2236-2240[PMID:10364591]
30 Shuber AP,Asca?o JJ,Boynton KA,Mitchell A,Frierson HF,El-Rifai W,Powell SM.Accurate,noninvasive detection of Helicobacter pylori DNA from stool samples:potential usefulness for monitoring treatment.J Clin Microbiol 2002;40:262-264[PMID:11773127]
31 Wi?niewska M,Nilsson HO,Bak-Romaniszyn L,Rechciński T,Bielański W,P?aneta-Ma?ecka I,P?onka M,Konturek S,Wadstr?m T,Rudnicka W,Chmiela M.Detection of specific Helicobacter pylori DNA and antigens in stool samples in dyspeptic patients and healthy subjects.Microbiol Immunol 2002;46:657-665[PMID:12477244]
32 Scaletsky IC,Aranda KR,Garcia GT,Gon?alves ME,Cardoso SR,Iriya K,Silva NP.Application of real-time PCR stool assay for Helicobacter pylori detection and clarithromycin susceptibility testing in Brazilian children.Helicobacter 2011;16:311-315[PMID:21762271 DOI:10.1111/j.1523-5378.2011.00845.x]
33 Noguchi N,Rimbara E,Kato A,Tanaka A,Tokunaga K,Kawai T,Takahashi S,Sasatsu M.Detection of mixed clarithromycinresistant and-susceptible Helicobacter pylori using nested PCRand direct sequencing of DNA extracted from faeces.J Med Microbiol 2007;56:1174-1180[PMID:17761479 DOI:10.1099/jmm.0.47302-0]
34 Rimbara E,Tamura R,Tanuma M,Noguchi N,Kawai T,Sasatsu M.Evaluation of clarithromycin resistance in Helicobacter pylori obtained from culture isolates,gastric juice,and feces.Helicobacter 2009;14:156-157[PMID:19298344 DOI:10.1111/j.1523-5378.2009.00663.x]
35 Booka M,Okuda M,Shin K,Miyashiro E,Hayashi H,Yamauchi K,Tamura Y,Yoshikawa N.Polymerase chain reaction--restriction fragment length polymorphism analysis of clarithromycin-resistant Helicobacter pylori infection in children using stool sample.Helicobacter 2005;10:205-213[PMID:15904478]
36 Schabereiter-Gurtner C,Hirschl AM,Dragosics B,Hufnagl P,Puz S,Kovách Z,Rotter M,Makristathis A.Novel real-time PCR assay for detection of Helicobacter pylori infection and simultaneous clarithromycin susceptibility testing of stool and biopsy specimens.J Clin Microbiol 2004;42:4512-4518[PMID:15472302]
37 Fontana C,Favaro M,Pietroiusti A,Pistoia ES,Galante A,Favalli C.Detection of clarithromycin-resistant Helicobacter pylori in stool samples.J Clin Microbiol 2003;41:3636-3640[PMID:12904368]
38 Vécsei A,Innerhofer A,Binder C,Gizci H,Hammer K,Bruckdorfer A,Riedl S,Gadner H,Hirschl AM,Makristathis A.Stool polymerase chain reaction for Helicobacter pylori detection and clarithromycin susceptibility testing in children.Clin Gastroenterol Hepatol 2010;8:309-312[PMID:20005978 DOI:10.1016/j.cgh.2009.12.002]
39 S m i t h S M,O’M o r a i n C,M c N a m a r a D.A n t i m i c r o b i a l susceptibility testing for Helicobacter pylori in times of increasing antibiotic resistance.World J Gastroenterol 2014;20:9912-9921[PMID:25110421 DOI:10.3748/wjg.v20.i29.9912]
40 Mégraud F,Bénéjat L,Ontsira Ngoyi EN,Lehours P.Molecular Approaches to Identify Helicobacter pylori Antimicrobial Resistance.Gastroenterol Clin North Am 2015;44:577-596[PMID:26314669 DOI:10.1016/j.gtc.2015.05.002]
41 Brennan DE,Omorogbe J,Hussey M,Tighe D,Holleran G,O’Morain C,Smith SM,Mc Namara D.Molecular detection of Helicobacter pylori antibiotic resistance in stool vs biopsy samples.World J Gastroenterol 2016;22:9214-9221[PMID:27895408DOI:10.3748/wjg.v22.i41.9214]
42 Giorgio F,Ierardi E,Sorrentino C,Principi M,Barone M,Losurdo G,Iannone A,Giangaspero A,Monno R,Di Leo A.Helicobacter pylori DNA isolation in the stool:an essential pre-requisite for bacterial noninvasive molecular analysis.Scand J Gastroenterol2016;51:1429-1432[PMID:27687850 DOI:10.1080/00365521.2016.1216592]
2 O’Connor A,Gisbert JP,O’Morain C,Ladas S.Treatment of Helicobacter pylori Infection 2015.Helicobacter 2015;20 Suppl 1:54-61[PMID:26372826 DOI:10.1111/hel.12258]
3 Ierardi E,Giorgio F,Losurdo G,Di Leo A,Principi M.How antibiotic resistances could change Helicobacter pylori treatment:Amatter of geography?World J Gastroenterol 2013;19:8168-8180[PMID:24363506 DOI:10.3748/wjg.v19.i45.8168]
4 Georgopoulos SD,Papastergiou V,Karatapanis S.Current options for the treatment of Helicobacter pylori.Expert Opin Pharmacother 2013;14:211-223[PMID:23331077 DOI:10.1517/14656566.2013.763926]
5 De Francesco V,Giorgio F,Hassan C,Manes G,Vannella L,Panella C,Ierardi E,Zullo A.Worldwide H.pylori antibiotic resistance:a systematic review.J Gastrointestin Liver Dis 2010;19:409-414[PMID:21188333]
6 Mégraud F.H pylori antibiotic resistance:prevalence,importance,and advances in testing.Gut 2004;53:1374-1384[PMID:15306603]
7 De Francesco V,Margiotta M,Zullo A,Hassan C,Troiani L,Burattini O,Stella F,Di Leo A,Russo F,Marangi S,Monno R,Stoppino V,Morini S,Panella C,Ierardi E.Clarithromycinresistant genotypes and eradication of Helicobacter pylori.Ann Intern Med 2006;144:94-100[PMID:16418408]
8 De Francesco V,Zullo A,Giorgio F,Saracino I,Zaccaro C,Hassan C,Ierardi E,Di Leo A,Fiorini G,Castelli V,Lo Re G,Vaira D.Change of point mutations in Helicobacter pylori r RNA associated with clarithromycin resistance in Italy.J Med Microbiol 2014;63:453-457[PMID:24344205 DOI:10.1099/jmm.0.067942-0]
9 Liou JM,Chang CY,Sheng WH,Wang YC,Chen MJ,Lee YC,Hung HW,Chian H,Chang SC,Wu MS,Lin JT.Genotypic resistance in Helicobacter pylori strains correlates with susceptibility test and treatment outcomes after levofloxacin-and clarithromycin-based therapies.Antimicrob Agents Chemother2011;55:1123-1129[PMID:21189342DOI:10.1128/AAC.01131-10]
10 Fallone CA,Chiba N,van Zanten SV,Fischbach L,Gisbert JP,Hunt RH,Jones NL,Render C,Leontiadis GI,Moayyedi P,Marshall JK.The Toronto Consensus for the Treatment of Helicobacter pylori Infection in Adults.Gastroenterology2016;151:51-69.e14[PMID:27102658DOI:10.1053/j.gastro.2016.04.006]
11 Malfertheiner P,Megraud F,O’Morain CA,Gisbert JP,Kuipers EJ,Axon AT,Bazzoli F,Gasbarrini A,Atherton J,Graham DY,Hunt R,Moayyedi P,Rokkas T,Rugge M,Selgrad M,Suerbaum S,Sugano K,El-Omar EM.Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report.Gut 2017;66:6-30[PMID:27707777 DOI:10.1136/gutjnl-2016-312288]
12 Fock KM,Katelaris P,Sugano K,Ang TL,Hunt R,Talley NJ,Lam SK,Xiao SD,Tan HJ,Wu CY,Jung HC,Hoang BH,Kachintorn U,Goh KL,Chiba T,Rani AA.Second Asia-Pacific Consensus Guidelines for Helicobacter pylori infection.J Gastroenterol Hepatol 2009;24:1587-1600[PMID:19788600 DOI:10.1111/j.1440-1746.2009.05982.x]
13 Lee M,Kemp JA,Canning A,Egan C,Tataronis G,Farraye FA.A randomized controlled trial of an enhanced patient compliance program for Helicobacter pylori therapy.Arch Intern Med 1999;159:2312-2316
14 Zullo A,Hassan C,De Francesco V,Repici A,Manta R,Tomao S,Annibale B,Vaira D.Helicobacter pylori and functional dyspepsia:an unsolved issue?World J Gastroenterol 2014;20:8957-8963[PMID:25083068 DOI:10.3748/wjg.v20.i27.8957]
15 Megraud F,Coenen S,Versporten A,Kist M,Lopez-Brea M,Hirschl AM,Andersen LP,Goossens H,Glupczynski Y.Helicobacter pylori resistance to antibiotics in Europe and its relationship to antibiotic consumption.Gut 2013;62:34-42[PMID:22580412 DOI:10.1136/gutjnl-2012-302254]
16 Graham DY,Lee SY.How to Effectively Use Bismuth Quadruple Therapy:The Good,the Bad,and the Ugly.Gastroenterol Clin North Am 2015;44:537-563[PMID:26314667 DOI:10.1016/j.gtc.2015.05.003]
17 Graham DY,Lee YC,Wu MS.Rational Helicobacter pylori therapy:evidence-based medicine rather than medicine-based evidence.Clin Gastroenterol Hepatol 2014;12:177-186.e3;Discussion e12-3[PMID:23751282]
18 Losurdo G,Giorgio F,Iannone A,Principi M,Barone M,Di Leo A,Ierardi E.Role of concomitant therapy for Helicobacter pylori eradication:A technical note.World J Gastroenterol 2016;22:8638-8640[PMID:27784977 DOI:10.3748/wjg.v22.i38.8638]
19 Wenzhen Y,Yumin L,Quanlin G,Kehu Y,Lei J,Donghai W,Lijuan Y.Is antimicrobial susceptibility testing necessary before first-line treatment for Helicobacter pylori infection?Meta-analysis of randomized controlled trials.Intern Med 2010;49:1103-1109[PMID:20558925]
20 López-Góngora S,Puig I,Calvet X,Villoria A,Baylina M,Mu?oz N,Sanchez-Delgado J,Suarez D,García-Hernando V,Gisbert JP.Systematic review and meta-analysis:susceptibility-guided versus empirical antibiotic treatment for Helicobacter pylori infection.JAntimicrob Chemother 2015;70:2447-2455[PMID:26078393DOI:10.1093/jac/dkv155]
21 Ferenc S,Gnus J,Ko?cielna M,Kinda M,Yarka A,Stewart L,Witkiewicz W.High antibiotic resistance of Helicobacter pylori and its effect on tailored and empiric eradication of the organism in Lower Silesia,Poland.Helicobacter 2017;22:[PMID:27879042DOI:10.1111/hel.12365]
22 Zhou L,Zhang J,Song Z,He L,Li Y,Qian J,Bai P,Xue Y,Wang Y,Lin S.Tailored versus Triple plus Bismuth or Concomitant Therapy as Initial Helicobacter pylori Treatment:A Randomized Trial.Helicobacter 2016;21:91-99[PMID:26104022 DOI:10.1111/hel.12242]
23 Kj?ller M,Fischer A,Justesen T.Transport conditions and number of biopsies necessary for culture of Helicobacter pylori.Eur J Clin Microbiol Infect Dis 1991;10:166-167[PMID:2060517]
24 Monno R,Giorgio F,Carmine P,Soleo L,Cinquepalmi V,Ierardi E.Helicobacter pylori clarithromycin resistance detected by Etest and Taq Man real-time polymerase chain reaction:a comparative study.APMIS 2012;120:712-717[PMID:22882260 DOI:10.1111/j.1600-0463.2012.02896.x]
25 De Francesco V,Margiotta M,Zullo A,Hassan C,Valle ND,Burattini O,Cea U,Stoppino G,Amoruso A,Stella F,Morini S,Panella C,Ierardi E.Primary clarithromycin resistance in Italy assessed on Helicobacter pylori DNA sequences by Taq Man real-time polymerase chain reaction.Aliment Pharmacol Ther 2006;23:429-435[PMID:16423002 DOI:10.1111/j.1365-2036.2006.02769.x]
26 De Francesco V,Zullo A,Ierardi E,Giorgio F,Perna F,Hassan C,Morini S,Panella C,Vaira D.Phenotypic and genotypic Helicobacter pylori clarithromycin resistance and therapeutic outcome:benefits and limits.J Antimicrob Chemother 2010;65:327-332[PMID:20008044 DOI:10.1093/jac/dkp445]
27 Ierardi E,Giorgio F,Losurdo G,Sorrentino C,Principi M,Di Leo A.Detection of Helicobacter pylori DNA sequences in gastric biopsy samples to refine the diagnosis and therapy.J Med Microbiol 2015;64:788-789[PMID:25934547 DOI:10.1099/jmm.0.000075]
28 Notarnicola M,Russo F,Cavallini A,Bianco M,Jirillo E,Pece S,Leoci C,Di Matteo G,Di Leo A.PCR identification of Helicobacter pylori in faeces from patients with gastroduodenal pathology.Med Sci Res 1996;24:785-787
29 Gramley WA,Asghar A,Frierson HF,Powell SM.Detection of Helicobacter pylori DNA in fecal samples from infected individuals.J Clin Microbiol 1999;37:2236-2240[PMID:10364591]
30 Shuber AP,Asca?o JJ,Boynton KA,Mitchell A,Frierson HF,El-Rifai W,Powell SM.Accurate,noninvasive detection of Helicobacter pylori DNA from stool samples:potential usefulness for monitoring treatment.J Clin Microbiol 2002;40:262-264[PMID:11773127]
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