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Souque C, González Ojeda I, Baym M. From Petri Dishes to Patients to Populations: Scales and Evolutionary Mechanisms Driving Antibiotic Resistance. Annu Rev Microbiol 2024; 78:361-382. [PMID: 39141706 DOI: 10.1146/annurev-micro-041522-102707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/16/2024]
Abstract
Tackling the challenge created by antibiotic resistance requires understanding the mechanisms behind its evolution. Like any evolutionary process, the evolution of antimicrobial resistance (AMR) is driven by the underlying variation in a bacterial population and the selective pressures acting upon it. Importantly, both selection and variation will depend on the scale at which resistance evolution is considered (from evolution within a single patient to the host population level). While laboratory experiments have generated fundamental insights into the mechanisms underlying antibiotic resistance evolution, the technological advances in whole genome sequencing now allow us to probe antibiotic resistance evolution beyond the lab and directly record it in individual patients and host populations. Here we review the evolutionary forces driving antibiotic resistance at each of these scales, highlight gaps in our current understanding of AMR evolution, and discuss future steps toward evolution-guided interventions.
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Affiliation(s)
- Célia Souque
- Departments of Biomedical Informatics and Microbiology, Harvard Medical School, Boston, Massachusetts, USA; ,
| | - Indra González Ojeda
- Departments of Biomedical Informatics and Microbiology, Harvard Medical School, Boston, Massachusetts, USA; ,
| | - Michael Baym
- Departments of Biomedical Informatics and Microbiology, Harvard Medical School, Boston, Massachusetts, USA; ,
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Smith SM, Boyle B, Buckley M, Costigan C, Doyle M, Farrell R, Ismail MS, Kevans D, Nugent S, O’Connor A, O’Morain C, Parihar V, Ryan C, McNamara D. The second Irish Helicobacter pylori Working Group consensus for the diagnosis and treatment of Helicobacter pylori infection in adult patients in Ireland. Eur J Gastroenterol Hepatol 2024; 36:1000-1009. [PMID: 38829956 PMCID: PMC11198963 DOI: 10.1097/meg.0000000000002796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 05/08/2024] [Indexed: 06/05/2024]
Abstract
BACKGROUND There has been an increase in resistance to many of the antimicrobials used to treat Helicobacter pylori ( H. pylori ) nationally and internationally. Primary clarithromycin resistance and dual clarithromycin and metronidazole resistance are high in Ireland. These trends call for an evaluation of best-practice management strategies. OBJECTIVE The objective of this study was to revise the recommendations for the management of H. pylori infection in adult patients in the Irish healthcare setting. METHODS The Irish H. pylori working group (IHPWG) was established in 2016 and reconvened in 2023 to evaluate the most up-to-date literature on H. pylori diagnosis, eradication rates and antimicrobial resistance. The 'GRADE' approach was then used to rate the quality of available evidence and grade the resulting recommendations. RESULTS The Irish H. pylori working group agreed on 14 consensus statements. Key recommendations include (1) routine antimicrobial susceptibility testing to guide therapy is no longer recommended other than for clarithromycin susceptibility testing for first-line treatment (statements 6 and 9), (2) clarithromycin triple therapy should only be prescribed as first-line therapy in cases where clarithromycin susceptibility has been confirmed (statement 9), (3) bismuth quadruple therapy (proton pump inhibitor, bismuth, metronidazole, tetracycline) is the recommended first-line therapy if clarithromycin resistance is unknown or confirmed (statement 10), (4) bismuth quadruple therapy with a proton pump inhibitor, levofloxacin and amoxicillin is the recommended second-line treatment (statement 11) and (5) rifabutin amoxicillin triple therapy is the recommend rescue therapy (statement 12). CONCLUSION These recommendations are intended to provide the most relevant current best-practice guidelines for the management of H. pylori infection in adults in Ireland.
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Affiliation(s)
| | - Breida Boyle
- Department of Clinical Microbiology, St. James’s Hospital, Dublin
| | - Martin Buckley
- Department of Gastroenterology, Mercy University Hospital, Cork
| | - Conor Costigan
- School of Medicine, Trinity College Dublin
- Department of Gastroenterology, Tallaght University Hospital, Dublin
| | - Maeve Doyle
- Department of Microbiology, University Hospital Waterford, Waterford
| | - Richard Farrell
- Department of Gastroenterology, Connolly Hospital, RCSI, Dublin
| | | | - David Kevans
- School of Medicine, Trinity College Dublin
- Department of Gastroenterology, St. James’s Hospital, Dublin
| | - Sean Nugent
- Department of Gastroenterology, Whitfield Clinic, Waterford
| | - Anthony O’Connor
- School of Medicine, Trinity College Dublin
- Department of Gastroenterology, Tallaght University Hospital, Dublin
| | | | - Vikrant Parihar
- Department of Gastroenterology, Letterkenny University Hospital
| | - Cristín Ryan
- School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin, Ireland
| | - Deirdre McNamara
- School of Medicine, Trinity College Dublin
- Department of Gastroenterology, Tallaght University Hospital, Dublin
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Fischbach W, Bornschein J, Hoffmann JC, Koletzko S, Link A, Macke L, Malfertheiner P, Schütte K, Selgrad DM, Suerbaum S, Schulz C. Update S2k-Guideline Helicobacter pylori and gastroduodenal ulcer disease of the German Society of Gastroenterology, Digestive and Metabolic Diseases (DGVS). ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:261-321. [PMID: 38364851 DOI: 10.1055/a-2181-2225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/18/2024]
Affiliation(s)
| | - Jan Bornschein
- Translational Gastroenterology Unit John, John Radcliffe Hospital Oxford University Hospitals, Oxford, United Kingdom
| | - Jörg C Hoffmann
- Medizinische Klinik I, St. Marien- und St. Annastiftskrankenhaus, Ludwigshafen, Deutschland
| | - Sibylle Koletzko
- Kinderklinik und Kinderpoliklinik im Dr. von Haunerschen Kinderspital, LMU-Klinikum Munich, Munich, Deutschland
- Department of Paediatrics, Gastroenterology and Nutrition, School of Medicine Collegium Medicum University of Warmia and Mazury, 10-719 Olsztyn, Poland
| | - Alexander Link
- Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum Magdeburg, Magdeburg, Deutschland
| | - Lukas Macke
- Medizinische Klinik und Poliklinik II Campus Großhadern, Universitätsklinikum Munich, Munich, Deutschland
- Deutsches Zentrum für Infektionsforschung, Standort Munich, Munich, Deutschland
| | - Peter Malfertheiner
- Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum Magdeburg, Magdeburg, Deutschland
- Medizinische Klinik und Poliklinik II Campus Großhadern, Universitätsklinikum Munich, Munich, Deutschland
| | - Kerstin Schütte
- Klinik für Allgemeine Innere Medizin und Gastroenterologie, Niels-Stensen-Kliniken Marienhospital Osnabrück, Osnabrück, Deutschland
| | - Dieter-Michael Selgrad
- Medizinische Klinik Gastroenterologie und Onkologie, Klinikum Fürstenfeldbruck, Fürstenfeldbruck, Deutschland
- Klinik für Innere Medizin 1, Universitätsklinikum Regensburg, Regensburg, Deutschland
| | - Sebastian Suerbaum
- Universität Munich, Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, Munich, Deutschland
- Nationales Referenzzentrum Helicobacter pylori, Pettenkoferstr. 9a, 80336 Munich, Deutschland
- Deutsches Zentrum für Infektionsforschung, Standort Munich, Munich, Deutschland
| | - Christian Schulz
- Medizinische Klinik und Poliklinik II Campus Großhadern, Universitätsklinikum Munich, Munich, Deutschland
- Deutsches Zentrum für Infektionsforschung, Standort Munich, Munich, Deutschland
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Lin K, Huang L, Wang Y, Li K, Ye Y, Yang S, Li A. Efficacy of genotypic susceptibility-guided tailored therapy for Helicobacter pylori infection: A systematic review and single arm meta-analysis. Helicobacter 2023; 28:e13015. [PMID: 37634236 DOI: 10.1111/hel.13015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Revised: 07/28/2023] [Accepted: 08/01/2023] [Indexed: 08/29/2023]
Abstract
BACKGROUND AND AIM The prevalence of antibiotic resistance for Helicobacter pylori (H. pylori) has been increasing over the year, making it more difficult for traditional empirical therapy to successfully eradicate H. pylori. Thus, tailored therapy (TT) guided by molecular-based antibiotic susceptibility testing (AST) has been frequently recommended. We conducted a single-arm meta-analysis to determine the efficacy of tailored therapy guided by molecular-based AST. METHODS A systematic literature review was performed on multiple databases, and studies on molecular-based TT were included. The eradication rates of TT by intention-to-treat (ITT) and per-protocol (PP) analyses were pooled respectively. RESULTS A total of 35 studies from 31 literature (4626 patients) were included in the single-arm meta-analysis. Overall, the pooled eradication rate of TT was 86.9% (95% CI:84.7%-89.1%) by the ITT analysis, and 91.5% (95% CI:89.8%-93.2%) by PP analysis. The pooled eradication rates of first-line TT and rescue TT were 86.6% and 85.1% by ITT analysis and 92.0% and 87.9% by PP analysis, respectively. When tailored rescue therapy was based on the genotypic resistance to at least four antibiotics, the pooled eradication rates reached 89.4% by ITT analysis and 92.1% by PP analysis. For genotype-susceptive strains, the pooled eradication rate of TT with targeted antibiotics was 93.1% (95% CI:91.3%-94.9%), among which the pooled eradication rate of tailored bismuth quadruple therapy was the highest (94.3%). Besides, the eradication rate of 7-day TT or tailored triple therapy without bismuth for genotype-susceptive strains could both reach more than 93.0%. CONCLUSION Tailored therapy guided by molecular-based AST can achieve somewhat ideal therapeutic outcomes. TT with a 7-day duration or without bismuth for genotype-susceptible strains can achieve good eradication efficacy. The effectiveness of TT can be improved to some extent by expanding the coverage of AST or by adding bismuth.
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Affiliation(s)
- Kaihao Lin
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lifang Huang
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yadong Wang
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Gastroenterology, Laboratory Department of Baiyun Branch, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Kangkang Li
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yuanning Ye
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Siqi Yang
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Aimin Li
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Department of Digestive Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Jearth V, Panigrahi MK. Current paradigms in the management of refractory Helicobacter pylori infection. Indian J Gastroenterol 2023; 42:766-779. [PMID: 37737326 DOI: 10.1007/s12664-023-01448-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 08/09/2023] [Indexed: 09/23/2023]
Abstract
Helicobacter pylori is the most prevalent chronic bacterial infection, with approximately half of the world's population estimated to be colonized. The World Health Organization (WHO) has classified Helicobacter pylori as a class-I carcinogen. All main society guidelines recommend its eradication in infected individuals. The global trend indicates that eradication rates are decreasing annually and the likelihood of eradication decreases with each unsuccessful therapeutic attempt. Resistance to antibiotics in H. pylori strains is the leading cause for eradication failure. Still, drug resistance and treatment failure may be complex, multi-dimensional and associated with several other factors. Knowledge of these factors can aid in optimizing eradication rates. This review will focus on the factors associated with refractory H. pylori, with a particular emphasis on antibiotic resistance mechanisms and their clinical implications. Also, the most recent literature and recommendations available for determining an appropriate regimen after the failure of the first attempt at eradication will be discussed.
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Affiliation(s)
- Vaneet Jearth
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Manas Kumar Panigrahi
- Department of Gastroenterology, All India Institute of Medical Sciences, Sijua, Patrapada, Bhubaneswar, 751 019, India.
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Costache C, Colosi HA, Grad S, Paștiu AI, Militaru M, Hădărean AP, Țoc DA, Neculicioiu VS, Baciu AM, Opris RV, Dumitrașcu DL, Colosi IA. Antibiotic Resistance in Helicobacter pylori Isolates from Northwestern and Central Romania Detected by Culture-Based and PCR-Based Methods. Antibiotics (Basel) 2023; 12:1672. [PMID: 38136706 PMCID: PMC10740699 DOI: 10.3390/antibiotics12121672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 11/24/2023] [Accepted: 11/25/2023] [Indexed: 12/24/2023] Open
Abstract
Little evidence has been published regarding the antimicrobial resistance patterns of Helicobacter pylori (H. pylori) strains in Northwestern and Central Romania. The aim of this study was to determine the antibiotic resistance pattern of H. pylori isolates from gastric biopsies collected from patients living in Romania using ETEST® and GenoType HelicoDR. Gastric biopsies were obtained from 148 adult patients, 87 women and 61 men, the majority (131 patients) from Northwestern and Central Romania. Sixty-nine H. pylori strains were detected by both culture and PCR; sixty-three biopsies were negative by both techniques; one biopsy was positive by culture but negative by PCR; and fifteen biopsies were negative by culture but positive by PCR. Primary resistance against clarithromycin, fluoroquinolones, and metronidazole was found in 16.7%, 11.1%, and 13.3% of strains, respectively. No primary resistance has been detected against amoxicillin, tetracycline, and rifampicin. Secondary resistance against clarithromycin, fluoroquinolones, metronidazole, amoxicillin, tetracycline, and rifampicin was found in 75.8%, 30.3%, 65.5%, 1.8%, 1.8%, and 7.3% of the strains, respectively. The most frequent clarithromycin-resistant genotype detected by GenoType HelicoDR was A2147G (62.3%). Concordances between ETEST® and PCR for clarithromycin and fluoroquinolones were 85.5% and 78.3%, respectively. Further investigation of H. pylori resistance should be conducted to ensure proper eradication schemes.
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Affiliation(s)
- Carmen Costache
- Department of Molecular Sciences, Division of Microbiology, Iuliu Hațieganu University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (C.C.); (A.M.B.)
- Cluj County Emergency Hospital, 400000 Cluj-Napoca, Romania; (S.G.)
| | - Horațiu Alexandru Colosi
- Department of Medical Education, Division of Medical Informatics and Biostatistics, Iuliu Hațieganu University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
| | - Simona Grad
- Cluj County Emergency Hospital, 400000 Cluj-Napoca, Romania; (S.G.)
- Department of Internal Medicine, 2nd Medical Clinic, Iuliu Hațieganu University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania
| | - Anamaria Ioana Paștiu
- Department of Genetics and Hereditary Diseases, Faculty of Veterinary Medicine, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, 400372 Cluj-Napoca, Romania
| | - Mariela Militaru
- Department of Molecular Sciences, Division of Medical Genetics, Iuliu Hatieganu University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania;
- Regina Maria Regional Laboratory, Medical Genetics Division, Regina Maria Private Health Network, Unirea Medical Center, 400363 Cluj-Napoca, Romania;
| | - Anca Paula Hădărean
- Regina Maria Regional Laboratory, Medical Genetics Division, Regina Maria Private Health Network, Unirea Medical Center, 400363 Cluj-Napoca, Romania;
| | - Dan Alexandru Țoc
- Department of Molecular Sciences, Division of Microbiology, Iuliu Hațieganu University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (C.C.); (A.M.B.)
| | - Vlad Sever Neculicioiu
- Department of Molecular Sciences, Division of Microbiology, Iuliu Hațieganu University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (C.C.); (A.M.B.)
| | - Alina Mihaela Baciu
- Department of Molecular Sciences, Division of Microbiology, Iuliu Hațieganu University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (C.C.); (A.M.B.)
| | - Razvan Vlad Opris
- Department of Molecular Sciences, Division of Microbiology, Iuliu Hațieganu University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (C.C.); (A.M.B.)
| | - Dan Lucian Dumitrașcu
- Cluj County Emergency Hospital, 400000 Cluj-Napoca, Romania; (S.G.)
- Department of Internal Medicine, 2nd Medical Clinic, Iuliu Hațieganu University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania
| | - Ioana Alina Colosi
- Department of Molecular Sciences, Division of Microbiology, Iuliu Hațieganu University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (C.C.); (A.M.B.)
- Regina Maria Regional Laboratory, Laboratory Medicine Division, Regina Maria Private Health Network, Unirea Medical Center, 400363 Cluj-Napoca, Romania
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Erkihun M, Chanie DN, Siraj YA. Antimicrobial-Resistance Profile of Helicobacter pylori, Obtained from Endoscopic Patients in Bahir Dar, North West Ethiopia. THE CANADIAN JOURNAL OF INFECTIOUS DISEASES & MEDICAL MICROBIOLOGY = JOURNAL CANADIEN DES MALADIES INFECTIEUSES ET DE LA MICROBIOLOGIE MEDICALE 2023; 2023:7326288. [PMID: 38023659 PMCID: PMC10661867 DOI: 10.1155/2023/7326288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 10/20/2023] [Accepted: 10/26/2023] [Indexed: 12/01/2023]
Abstract
Background Antimicrobial resistance for Helicobacter pylori infection is a highly emerging problem throughout the world to treat gastric-associated diseases. People living in developing countries are more likely to acquire a Helicobacter pylori infection and less likely to gate treatment after infection due to poverty. Therefore, the current study was aimed at determining the magnitude and antibiotic-resistance profile of Helicobacter pylori isolated from patients who underwent endoscopic examination. Methods A cross-sectional study was conducted from January to May 2019 at endoscopy service-providing health facilities that are found in Bahir Dar, Ethiopia (Gamby teaching general hospital, Kidane Mihret specialty higher clinic, and Eyasta specialty higher clinic). Data were collected using a pretested, structured questionnaire. Antibiotic susceptibility of Helicobacter pylori isolates from gastric biopsies was determined. Data were analyzed using SPSS version 23. Results The 17.8% proportion of Helicobacter pylori was isolated from 135 endoscopy-examined patients (24/135). The majority of isolates (71% of 17/24) were from males, while only 29% of 7/24) were from females. Antimicrobial-resistance of Helicobacter pylori was high to all commonly prescribed antibiotics: amoxicillin and metronidazole (91.7%), clarithromycin and ciprofloxacin (66.7% each), and tetracycline (37.5%). Conclusion Helicobacter pylori isolates from the current study participants were rather low in number. But the highest antibiotic-resistance profile of Helicobacter pylori was observed. Therefore, these findings alarmingly indicate that routine antimicrobial susceptibility testing against Helicobacter pylori isolates is crucial for better patient management.
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Affiliation(s)
- Mulat Erkihun
- Department of Medical Laboratory Sciences, School of Health Sciences, College of Medicine and Health Sciences, Debre Tabor University, P.O. Box 272, Debre Tabor, Ethiopia
| | - Desalegn Nigatu Chanie
- Department of Internal Medicine, School of Medicine, College of Medicine and Health Sciences, Bahir Dar University, P.O. Box 79, Bahir Dar, Ethiopia
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O'Morain C, Smith SM. Antimicrobial susceptibility testing for Helicobacter pylori comes of age. Lancet Gastroenterol Hepatol 2023; 8:593-595. [PMID: 37178704 DOI: 10.1016/s2468-1253(23)00113-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 04/19/2023] [Indexed: 05/15/2023]
Affiliation(s)
- Colm O'Morain
- School of Medicine, Trinity College Dublin, Dublin 2, Ireland.
| | - Sinead M Smith
- School of Medicine, Trinity College Dublin, Dublin 2, Ireland
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Aktualisierte S2k-Leitlinie Helicobacter
pylori und gastroduodenale Ulkuskrankheit der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) – Juli 2022 – AWMF-Registernummer: 021–001. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2023; 61:544-606. [PMID: 37146633 DOI: 10.1055/a-1975-0414] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/07/2023]
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Malfertheiner P, Camargo MC, El-Omar E, Liou JM, Peek R, Schulz C, Smith SI, Suerbaum S. Helicobacter pylori infection. Nat Rev Dis Primers 2023; 9:19. [PMID: 37081005 PMCID: PMC11558793 DOI: 10.1038/s41572-023-00431-8] [Citation(s) in RCA: 313] [Impact Index Per Article: 156.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/17/2023] [Indexed: 04/22/2023]
Abstract
Helicobacter pylori infection causes chronic gastritis, which can progress to severe gastroduodenal pathologies, including peptic ulcer, gastric cancer and gastric mucosa-associated lymphoid tissue lymphoma. H. pylori is usually transmitted in childhood and persists for life if untreated. The infection affects around half of the population in the world but prevalence varies according to location and sanitation standards. H. pylori has unique properties to colonize gastric epithelium in an acidic environment. The pathophysiology of H. pylori infection is dependent on complex bacterial virulence mechanisms and their interaction with the host immune system and environmental factors, resulting in distinct gastritis phenotypes that determine possible progression to different gastroduodenal pathologies. The causative role of H. pylori infection in gastric cancer development presents the opportunity for preventive screen-and-treat strategies. Invasive, endoscopy-based and non-invasive methods, including breath, stool and serological tests, are used in the diagnosis of H. pylori infection. Their use depends on the specific individual patient history and local availability. H. pylori treatment consists of a strong acid suppressant in various combinations with antibiotics and/or bismuth. The dramatic increase in resistance to key antibiotics used in H. pylori eradication demands antibiotic susceptibility testing, surveillance of resistance and antibiotic stewardship.
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Affiliation(s)
- Peter Malfertheiner
- Medical Department II, University Hospital, Ludwig-Maximilians-Universität, Munich, Germany.
- Medical Department Klinik of Gastroenterology, Hepatology and Infectiology, Otto-von-Guericke Universität, Magdeburg, Germany.
| | - M Constanza Camargo
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Emad El-Omar
- Microbiome Research Centre, St George & Sutherland Clinical Campuses, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia
| | - Jyh-Ming Liou
- Department of Internal Medicine, National Taiwan University Cancer Center, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Richard Peek
- Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Christian Schulz
- Medical Department II, University Hospital, Ludwig-Maximilians-Universität, Munich, Germany
- DZIF Deutsches Zentrum für Infektionsforschung, Partner Site Munich, Munich, Germany
| | - Stella I Smith
- Department of Molecular Biology and Biotechnology, Nigerian Institute of Medical Research, Yaba, Lagos, Nigeria
| | - Sebastian Suerbaum
- DZIF Deutsches Zentrum für Infektionsforschung, Partner Site Munich, Munich, Germany
- Max von Pettenkofer Institute, Faculty of Medicine, Ludwig-Maximilians-Universität, Munich, Germany
- National Reference Center for Helicobacter pylori, Munich, Germany
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Fekadu S, Engiso H, Seyfe S, Iizasa H, Godebo A, Deyno S, Yoshiyama H. Effectiveness of eradication therapy for Helicobacter pylori infection in Africa: a systematic review and meta-analysis. BMC Gastroenterol 2023; 23:55. [PMID: 36882697 PMCID: PMC9990047 DOI: 10.1186/s12876-023-02707-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 02/28/2023] [Indexed: 03/09/2023] Open
Abstract
BACKGROUND The effectiveness of Helicobacter pylori (H. pylori) eradication depends on the treatment protocol. This study investigates the H. pylori eradication rate in Africa using the best available evidence from databases. METHODS Databases were searched and results were pooled together. Heterogeneity between studies was assessed using I2 test statistics. Stata version 13 software was employed to compute the pooled eradication rate. In the subgroup analysis comparison, the finding is considered significant when the confidence intervals did not overlap. RESULTS Twenty-two studies from 9 African countries with a total population of 2,163 were included in this study. The pooled eradication rate of H. pylori was 79% (95% CI: 75%-82%), heterogeneity (I2 = 93.02%). In the subgroup analysis by study design, a higher eradication rate was reported from observational studies (85%, 95% CI: 79%-90%), compared to randomized control trials (77%, 95% CI: 73%-82%); by the duration of therapy, higher eradication rate was reported in 10-days regimen (88%, 95% CI: 84%-92%), compared to 7-days regimen (66%, 95% CI: 55%-77%); by country, the highest eradication rate was found in Ethiopia (90%; 95% CI: 87%-93%) and the lowest eradication rate was reported in Ivory Coast (22.3%; 95% CI:15%-29%); by type of H. pylori test, the highest eradication rate was reported when rapid urease test coupled with histology (88%, 95% CI: 77%-96%), and the lowest eradication rate was reported with histology alone (22.3%; 95% CI:15%-29%). Significant heterogeneity was observed with pooled prevalence (I2 = 93.02%, P < 0.000). CONCLUSIONS In Africa, the first-line therapy showed a variable eradication rate for H. pylori. This study demonstrates the necessity to optimize current H. pylori treatment regimens in each country, taking into account the antibiotic susceptibility. Future RCT studies with standardized regimens are warranted.
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Affiliation(s)
- Sintayehu Fekadu
- School of Laboratory Sciences, College of Medicine and Health Sciences, Hawassa University, P. O. Box 1560, Hawassa, Ethiopia.
| | - Hizkel Engiso
- School of Pharmacy, College of Medicine and Health Sciences, Hawassa University, P. O. Box 1560, Hawassa, Ethiopia
| | - Sisay Seyfe
- Department of Biochemistry, College of Medicine and Health Sciences, Hawassa University, P. O. Box 1560, Hawassa, Ethiopia
| | - Hisashi Iizasa
- Department of Microbiology, Faculty of Medicine, Shimane University, Shimane, Japan
| | - Ashebir Godebo
- Department of Soil Science, University of Saskatchewan, Saskatoon, SK, Canada
| | - Serawit Deyno
- School of Pharmacy, College of Medicine and Health Sciences, Hawassa University, P. O. Box 1560, Hawassa, Ethiopia
| | - Hironori Yoshiyama
- Department of Microbiology, Faculty of Medicine, Shimane University, Shimane, Japan
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Goni E, Tammer I, Schütte K, Thon C, Jechorek D, Mahajan UM, Vasapolli R, Macke L, Aulinger B, Selgrad M, Link A, Malfertheiner P, Schulz C. The influence of gastric atrophy on Helicobacter pylori antibiotics resistance in therapy-naïve patients. Front Microbiol 2022; 13:938676. [PMID: 36212809 PMCID: PMC9537355 DOI: 10.3389/fmicb.2022.938676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 08/29/2022] [Indexed: 01/06/2023] Open
Abstract
Background Antibiotic susceptibility of Helicobacter pylori to antibiotics may vary among different niches of the stomach. The progression of chronic H. pylori gastritis to atrophy changes intragastric physiology that may influence selection of resistant strains. Aim To study the antibiotic resistance of H. pylori taking the severity of atrophic gastritis in antrum and corpus into account. Methods Helicobacter pylori-positive patients (n = 110, m = 32, mean age 52.6 ± 13.9 years) without prior H. pylori eradication undergoing upper gastrointestinal (GI) endoscopy for dyspeptic symptoms were included in a prospective study. Patients were stratified into three groups depending on the grade of atrophy: no atrophy (OLGA Stage 0), mild atrophy (OLGA Stage I–II) and moderate/severe atrophy (OLGA Stage III–IV). Two biopsies each from the antrum and the corpus and one from the angulus were taken and assessed according to the updated Sydney system. H. pylori strains were isolated from antrum and corpus biopsies and tested for antibiotic susceptibility (AST) for amoxicillin, clarithromycin, metronidazole, levofloxacin, tetracycline, and rifampicin by the agar dilution methods. A Chi-square test of independence with a 95% confidence interval was used to detect differences in the proportion of patients with susceptible and resistant H. pylori strains. Results Among 110 patients, primary clarithromycin resistance (R) was 30.0%, both in the antrum and corpus; metronidazole resistance accounted for 36.4 and 34.5% in the antrum and corpus; and levofloxacin was 19.1 and 22.7% in the antrum and corpus, respectively. Resistance rates to amoxicillin, tetracycline, and rifampicin were below 5%. Dual antibiotic resistance rate was 21.8%, and triple resistance rate was 9.1%. There was a significant difference in the resistance rate distribution in antrum (p < 0.0001) and corpus (p < 0.0001). With increasing severity of atrophy according to OLGA stages, there was a significant increase in clarithromycin-R and metronidazole-R. Conclusion In treatment-naïve patients, antibiotic resistance and heteroresistance were related to the severity of atrophy. The high clarithromycin resistance in atrophic gastritis suggests that H. pylori antibiotic susceptibility testing should always be performed in this condition before selecting the eradication regimen.
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Affiliation(s)
- Elisabetta Goni
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Ina Tammer
- Otto-von-Guericke University Hospital, Institute of Medical Microbiology, Magdeburg, Germany
| | - Kerstin Schütte
- Department of Internal Medicine and Gastroenterology, Niels-Stensen-Kliniken, Marienhospital, Osnabrück, Germany
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Niedersachsen, Germany
| | - Cosima Thon
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
| | - Dörthe Jechorek
- Department of Pathology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
| | | | - Riccardo Vasapolli
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
- Deutsches Zentrum für Infektionsforschung (DZIF), Partner Site Munich, München, Germany
| | - Lukas Macke
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
- Deutsches Zentrum für Infektionsforschung (DZIF), Partner Site Munich, München, Germany
| | - Benedikt Aulinger
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Michael Selgrad
- Department of Internal Medicine, Klinikum Fuerstenfeldbrueck, Fuerstenfeldbrueck, Germany
- Department of Internal Medicine I, University Hospital of Regensburg, Regensburg, Germany
| | - Alexander Link
- Deutsches Zentrum für Infektionsforschung (DZIF), Partner Site Munich, München, Germany
| | - Peter Malfertheiner
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
| | - Christian Schulz
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
- Deutsches Zentrum für Infektionsforschung (DZIF), Partner Site Munich, München, Germany
- *Correspondence: Christian Schulz,
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13
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Ansari S, Yamaoka Y. Helicobacter pylori Infection, Its Laboratory Diagnosis, and Antimicrobial Resistance: a Perspective of Clinical Relevance. Clin Microbiol Rev 2022; 35:e0025821. [PMID: 35404105 PMCID: PMC9491184 DOI: 10.1128/cmr.00258-21] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Despite the recent decrease in overall prevalence of Helicobacter pylori infection, morbidity and mortality rates associated with gastric cancer remain high. The antimicrobial resistance developments and treatment failure are fueling the global burden of H. pylori-associated gastric complications. Accurate diagnosis remains the opening move for treatment and eradication of infections caused by microorganisms. Although several reports have been published on diagnostic approaches for H. pylori infection, most lack the data regarding diagnosis from a clinical perspective. Therefore, we provide an intensive, comprehensive, and updated description of the currently available diagnostic methods that can help clinicians, infection diagnosis professionals, and H. pylori researchers working on infection epidemiology to broaden their understanding and to select appropriate diagnostic methods. We also emphasize appropriate diagnostic approaches based on clinical settings (either clinical diagnosis or mass screening), patient factors (either age or other predisposing factors), and clinical factors (either upper gastrointestinal bleeding or partial gastrectomy) and appropriate methods to be considered for evaluating eradication efficacy. Furthermore, to cope with the increasing trend of antimicrobial resistance, a better understanding of its emergence and current diagnostic approaches for resistance detection remain inevitable.
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Affiliation(s)
- Shamshul Ansari
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu City, Oita, Japan
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu City, Oita, Japan
- Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, Texas, USA
- Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia
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14
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Keikha M, Karbalaei M. Prevalence of antibiotic heteroresistance associated with Helicobacter pylori infection: A systematic review and meta-analysis. Microb Pathog 2022; 170:105720. [PMID: 35964816 DOI: 10.1016/j.micpath.2022.105720] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 08/05/2022] [Accepted: 08/08/2022] [Indexed: 10/15/2022]
Abstract
BACKGROUND Heteroresistance is a general term to describe diverse responses to specific antibiotics that can occur due to infection with either multiple bacterial strains or microevolution of a single strain during chronic infection. Due to limited information regarding heteroresistance Helicobacter pylori (H. pylori) infection, the current study was carried out to evaluate the prevalence of this phenomenon. METHODS For this study, all potential relevant studies were collected by searching international databases such as ISI Web of Science, PubMed, Scopus, ScienceDirect, ProQuest, Embase, DOAJ, China National Knowledge Infrastructure (CNKI), and Google Scholar. Finally, the frequency of heteroresistance H. pylori infection was measured using the event rate corresponding to 95% confidence intervals. RESULTS A total of 26 studies met our criteria; the eligible studies were related to the years 2001-2022. Our results showed that the prevalence of heteroresistance H. pylori strains was 60.1% to clarithromycin, 61.1% to metronidazole, 46.1% to levofloxacin, 3.8% to amoxicillin, and 21.1% to tetracycline. Our literature review also showed discrepancy of antimicrobial susceptibility test in strains isolated from different anatomical sites of the stomach. Heteroresistance H. pylori infection in developing countries is mostly due to infection with multiple H. pylori strains, while in developed countries it is due to microevolution of a single H. pylori strain in response to antibiotic pressure. CONCLUSIONS Heteroresistance H. pylori infection interferes with successful therapy and eventually can lead to the treatment failure. If a biopsy is taken from only one gastric site, resistant strains of H. pylori may be underestimated. Considering the role of heteroresistance H. pylori infection in treatment failure, it is very important for gastroenterologists to improve their knowledge about this fact. Regardingly, new guidelines should be developed and designed for the management and treatment of heteroresistance H. pylori infection.
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Affiliation(s)
- Masoud Keikha
- Department of Microbiology and Virology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohsen Karbalaei
- Department of Microbiology and Virology, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran.
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15
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Kouhsari E, Sadeghifard N, Khadiv A, Sayadi H, Amiriani T, Ghafourian S, Valadbeigi H, Krutova M. Heteroresistance to clarithromycin and metronidazole in patients with a Helicobacter pylori infection: a systematic review and meta-analysis. Ann Clin Microbiol Antimicrob 2022; 21:19. [PMID: 35596211 PMCID: PMC9123761 DOI: 10.1186/s12941-022-00509-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 04/29/2022] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Antimicrobial resistance of H. pylori can lead to treatment failure. Importantly, several studies have reported on heteroresistance, i.e. the presence of resistant and susceptible H. pylori populations in the same sample and/or a difference in the susceptibility patterns between biopsy samples. This meta-analysis aims to provide comprehensive data on the prevalence of metronidazole and clarithromycin heteroresistance and the approaches to their detection. MATERIAL AND METHODS A systematic review was performed after the search of MEDLINE, Scopus and Web of Science. The study outcomes were the weighted pooled prevalence of heteroresistance to clarithromycin and metronidazole in H. pylori positive samples and/or isolates with a subanalysis by continent. RESULTS A total of 22 studies that had investigated 3852 H. pylori positive patients were included in the meta-analysis. Heteroresistance to clarithromycin was reported in 20 studies, with a weighted pooled prevalence of 6.8% (95% CI 5.1-8.6; 3654 H. pylori positive patients; the substantial heterogeneity I2 = 55.6%). Heteroresistance to metronidazole was reported in 12 studies, with a weighted pooled prevalence of 13.8% (95% CI 8.9-18.6; 1670 H. pylori positive patients; the substantial heterogeneity I2 = 60.9%). The weighted pooled prevalence of clarithromycin heteroresistance was similar in Asia and Europe (p = 0.174584), however, metronidazole heteroresistance was detected more often in Europe (p < 0.00001). Clarithromycin heteroresistance was detected more often by phenotype rather than by using genotyping methods (12 vs 8 studies), whereas heteroresistance to metronidazole was detected only by phenotype. CONCLUSION The prevalence of heteroresistance to clarithromycin and/or metronidazole is not negligible and can be detected in approximately 7 and 14% of H. pylori positive samples, respectively. These findings highlight the need to raise the awareness of gastroenterologists and microbiologists to the heteroresistance to clarithromycin and metronidazole in patients with a H. pylori infection.
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Affiliation(s)
- Ebrahim Kouhsari
- Laboratory Sciences Research Centre, Golestan University of Medical Sciences, Gorgan, Iran
| | - Nourkhoda Sadeghifard
- Clinical Microbiology Research Centre, Ilam University of Medical Sciences, Ilam, Iran
| | - Arezoo Khadiv
- Clinical Microbiology Research Centre, Ilam University of Medical Sciences, Ilam, Iran.,Department of Microbiology, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Hojjat Sayadi
- Non-Communicable Diseases Research Centre, Ilam University of Medical Sciences, Ilam, Iran
| | - Taghi Amiriani
- Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, Gorgan, Iran
| | - Sobhan Ghafourian
- Clinical Microbiology Research Centre, Ilam University of Medical Sciences, Ilam, Iran.,Department of Microbiology, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Hassan Valadbeigi
- Clinical Microbiology Research Centre, Ilam University of Medical Sciences, Ilam, Iran.
| | - Marcela Krutova
- Department of Medical Microbiology, Charles University, 2nd Faculty of Medicine and Motol University Hospital, Prague, Czech Republic
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Liu Y, Yang F, Wang S, Chi W, Ding L, Liu T, Zhu F, Ji D, Zhou J, Fang Y, Zhang J, Xiang P, Zhang Y, Zhao H. HopE and HopD Porin-Mediated Drug Influx Contributes to Intrinsic Antimicrobial Susceptibility and Inhibits Streptomycin Resistance Acquisition by Natural Transformation in Helicobacter pylori. Microbiol Spectr 2022; 10:e0198721. [PMID: 35234510 PMCID: PMC9045298 DOI: 10.1128/spectrum.01987-21] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 01/21/2022] [Indexed: 12/14/2022] Open
Abstract
Helicobacter pylori is a human pathogen competent for natural transformation. Intrinsic and acquired antibiotic resistance contribute to the survival and multiplication of H. pylori under antibiotics. While drug-resistance dissemination by natural transformation (NT)-mediated horizontal gene transfer remains poorly understood in H. pylori. The purpose of the study was to investigate the role of H. pylori porins (HopA, HopB, HopC, HopD, and HopE) in the intrinsic antibiotic resistance and to preliminarily reveal the potential effect of HopE and HopD porins in streptomycin resistance acquisition after NT in the presence of antibiotics. Using traditional antibiotic susceptibility tests and growth curve analysis, we found the MIC values of metronidazole, clarithromycin, levofloxacin, tetracycline, rifampin, and streptomycin in mutants lacking HopE and/or HopD were significantly elevated compare to those in wild-type strain. The quantitative analysis of the tetramethyl rhodamine isothiocyanate (TRITC)-labeled streptomycin accumulation at the single-cell level showed reduced streptomycin intracellular fluorescence in ΔhopE and ΔhopD mutant cells. Furthermore, in the presence of translation-inhibiting antibiotic streptomycin, the resistance acquisition frequency was decreased in the wild-type strain, which could be reversed by mutants lacking HopE and HopD that restored relatively high resistance acquisition frequencies. By transforming a pUC19-rpsLmut-sfgfp linear plasmid carrying a streptomycin conferring mutation, we observed that the impaired ability of rpsLmut synthesis in the wild-type strain was restored in the ΔhopE and ΔhopD mutant transformants. Our study revealed that in the presence of streptomycin, resistance acquisition at least partially relied on the deletion of the hopE and hopD genes, because their loss reduced streptomycin concentration in the cell and thus restored the expression of the resistance-conferring gene, which was inhibited by streptomycin in wild-type strain. The loss of HopE and HopD influx activity may also preserve resistance acquisition by transformation in the presence of antibiotics with other modes of action. IMPORTANCE Helicobacter pylori is constitutively competent for natural transformation (NT) and possesses an efficient system for homologous recombination, which could be utilized to study the NT-mediated horizontal gene transfer induced antibiotic resistance acquisition. Bacterial porins have drawn renewed attention because of their crucial role in antibiotic susceptibility. From the perspective of porin-mediated influx in H. pylori, our study preliminarily revealed the important role of HopE and HopD porins not only in preserving the intrinsic susceptibility to specific antibiotic but also in evading acquired antibiotic resistance by NT in the presence of translation-inhibiting antimicrobial. Therefore, the loss of HopE or HopD porin in H. pylori genomes, combined with the large number of secreted or cell-free genetic elements carrying mutations conferring antibiotic resistance, may raise the possibility that this mechanism plays a potential role in the propagation of antibiotic resistance within H. pylori communities.
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Affiliation(s)
- Yixin Liu
- Department of Laboratory Medicine, Huadong Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, China
- Research Center on Aging and Medicine, Fudan University, Shanghai, China
| | - Feng Yang
- Department of Laboratory Medicine, Huadong Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, China
- Research Center on Aging and Medicine, Fudan University, Shanghai, China
| | - Su Wang
- Department of Laboratory Medicine, Huadong Hospital, Fudan University, Shanghai, China
| | - Wenjing Chi
- Department of Laboratory Medicine, Huadong Hospital, Fudan University, Shanghai, China
| | - Li Ding
- Department of Laboratory Medicine, Huadong Hospital, Fudan University, Shanghai, China
| | - Tao Liu
- Department of Laboratory Medicine, Huadong Hospital, Fudan University, Shanghai, China
| | - Feng Zhu
- Department of Laboratory Medicine, Huadong Hospital, Fudan University, Shanghai, China
| | - Danian Ji
- Department of Endoscopy, Huadong Hospital, Fudan University, Shanghai, China
| | - Jun Zhou
- Department of Endoscopy, Huadong Hospital, Fudan University, Shanghai, China
| | - Yi Fang
- Department of Laboratory Medicine, Huadong Hospital, Fudan University, Shanghai, China
| | - Jinghao Zhang
- Department of Laboratory Medicine, Huadong Hospital, Fudan University, Shanghai, China
| | - Ping Xiang
- Department of Endoscopy, Huadong Hospital, Fudan University, Shanghai, China
| | - Yanmei Zhang
- Department of Laboratory Medicine, Huadong Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, China
- Research Center on Aging and Medicine, Fudan University, Shanghai, China
| | - Hu Zhao
- Department of Laboratory Medicine, Huadong Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, China
- Research Center on Aging and Medicine, Fudan University, Shanghai, China
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17
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Sharndama HC, Mba IE. Helicobacter pylori: an up-to-date overview on the virulence and pathogenesis mechanisms. Braz J Microbiol 2022; 53:33-50. [PMID: 34988937 PMCID: PMC8731681 DOI: 10.1007/s42770-021-00675-0] [Citation(s) in RCA: 83] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 12/24/2021] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori is an organism associated with ulcer disease and gastric cancer. The latter is one of the most prevalent malignancies and currently the fourth major cause of cancer-related deaths globally. The pathogen infects about 50% of the world population, and currently, no treatment ensures its total elimination. There has been an increase in our understanding of the pathophysiology and pathogenesis mechanisms of H. pylori over the years. H. pylori can induce several genetic alterations, express numerous virulence factors, and trigger diverse adaptive mechanisms during its adherence and colonization. For successful colonization and infection establishment, several effector proteins/toxins are released by the organism. Evidence is also available reporting spiral to coccoid transition as a unique tactic H. pylori uses to survive in the host's gastrointestinal tract (GIT). Thus, the virulence and pathogenicity of H. pylori are under the control of complex interplay between the virulence factors, host, and environmental factors. Expounding the role of the various virulence factors in H. pylori pathogenesis and clinical outcomes is crucial for vaccine development and in providing and developing a more effective therapeutic intervention. Here we critically reflect on H. pylori infection and delineate what is currently known about the virulence and pathogenesis mechanisms of H. pylori.
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Affiliation(s)
| | - Ifeanyi Elibe Mba
- Department of Microbiology, University of Nigeria, Nsukka, Enugu, Nigeria.
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18
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Increased Antibiotic Resistance in Children with Helicobacter pylori Infection: A Retrospective Study. Pathogens 2022; 11:pathogens11020178. [PMID: 35215122 PMCID: PMC8877488 DOI: 10.3390/pathogens11020178] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/15/2022] [Accepted: 01/24/2022] [Indexed: 02/07/2023] Open
Abstract
Children with recurrent abdominal pain may be suffering from a Helicobacterpylori (HP) infection. The gold standard for confirming HP gastritis is histological evaluation and microbiological tests performed on specimens collected by esophagogastroduodenoscopy (EGD). The aim of this study was to analyze HP positive cultures and antibiograms with regard to clinical and histopathological correlates. The data of 124 subjects with frequent gastrointestinal symptoms who underwent an EGD were retrospectively collected and analyzed. The mean age of the patients was 13 ± 3.6 years. The most frequent complaints were epigastric pain (84%; n = 100/119) and dyspepsia (79%; n = 94/119). HP gastritis was diagnosed in 54% (n = 67). Interestingly, 40% (n = 49) of the isolates were resistant to at least one antibiotic: amoxicillin (20%; n = 10/49), clarithromycin (45%; n = 22/49), or metronidazole (59%; n = 29/49). Isolates were resistant to two or more antibiotics in 16% (n = 20) of cases. In conclusion, we revealed remarkably high resistance rates to amoxicillin, metronidazole, and clarithromycin in our cohort. The presence of antibiotic resistance to more than one antibiotic was substantially increased in our HP-infected patients and this may negatively affect eradication treatment.
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19
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Brennan DE, O'Morain C, McNamara D, Smith SM. Combined antrum and corpus biopsy protocol improves Helicobacter pylori culture success. World J Gastrointest Pathophysiol 2022; 13:34-40. [PMID: 35116178 PMCID: PMC8788162 DOI: 10.4291/wjgp.v13.i1.34] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 10/16/2021] [Accepted: 01/14/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Helicobacter pylori (H. pylori) causes chronic gastritis, peptic ulcer disease, gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma. Eradication rates have fallen, mainly due to antimicrobial resistance. Consensus guidelines recommend that first-line treatment is based on the local prevalence of antimicrobial resistance and that rescue therapies are guided by antimicrobial susceptibility testing (AST). However, H. pylori culture is challenging and culture-based AST is not routinely performed in the majority of hospitals. Optimisation of H. pylori culture from clinical specimens will enable more widespread AST to determine the most appropriate antimicrobials for H. pylori eradication. AIM To determine whether dual antrum and corpus biopsy sampling is superior to single antrum biopsy sampling for H. pylori culture. METHODS The study received ethical approval from the joint research ethics committee of Tallaght University Hospital and St. James's Hospital. Patients referred for upper gastrointestinal endoscopy were invited to participate. Biopsies were collected in tubes containing Dent's transport medium and patient demographics were recorded. Biopsies were used to inoculate Colombia blood agar plates. Plates were incubated under microaerobic conditions and evaluated for the presence of H. pylori. Statistical analyses were performed using Graphpad PRISM. Continuous variables were compared using the two-tailed independent t-test. Categorical variables were compared using the two-tailed Fisher exact test. In all cases, a P value less than 0.05 was considered significant. RESULTS In all, samples from 219 H. pylori-infected patients were analysed in the study. The mean age of recruited patients was 48 ± 14.9 years and 50.7% (n = 111) were male. The most common endoscopic finding was gastritis (58.9%; n = 129). Gastric ulcer was diagnosed in 4.6% (n = 10) of patients, while duodenal ulcer was diagnosed in 2.7% (n = 6). Single antrum biopsies were collected from 73 patients, whereas combined antrum and corpus biopsies were collected from 146 patients. There was no significant difference in age, sex or endoscopic findings between the two groups. H. pylori was successfully cultured in a significantly higher number of cases when combined antrum and corpus biopsies were used compared to a single antrum biopsy [64.4% (n = 94/146) vs 49.3% (36/73); P = 0.04)]. CONCLUSION Combined corpus and antrum biopsy sampling improves H. pylori culture success compared to single antrum biopsy sampling.
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Affiliation(s)
- Denise E Brennan
- Department of Clinical Medicine, Trinity College Dublin, Trinity Centre, Tallaght University Hospital, Dublin D24, Ireland
| | - Colm O'Morain
- Department of Clinical Medicine, Trinity College Dublin, Trinity Centre, Tallaght University Hospital, Dublin D24, Ireland
| | - Deirdre McNamara
- Department of Clinical Medicine, Trinity College Dublin, Trinity Centre, Tallaght University Hospital, Dublin D24, Ireland
| | - Sinead M Smith
- Department of Clinical Medicine, Trinity College Dublin, Trinity Centre, Tallaght University Hospital, Dublin D24, Ireland
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20
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Moreno-Flores A, Potel-Alvarellos C, Álvarez-Fernández M. Helicobacter pylori, antimicrobial resistance evolution 2012-2020 in Vigo sanitary area, Pontevedra, Spain. ENFERMEDADES INFECCIOSAS Y MICROBIOLOGIA CLINICA (ENGLISH ED.) 2021; 39:523-524. [PMID: 34531160 DOI: 10.1016/j.eimce.2021.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 10/31/2020] [Indexed: 06/13/2023]
Affiliation(s)
- Antonio Moreno-Flores
- Servicio de Microbiología, Complejo Hospitalario Universitario de Vigo (Hospitales Álvaro Cunqueiro y Meixoeiro), Instituto de Investigación Sanitaria Galicia Sur (IISGS), Vigo, Pontevedra, Spain
| | - Carmen Potel-Alvarellos
- Servicio de Microbiología, Complejo Hospitalario Universitario de Vigo (Hospitales Álvaro Cunqueiro y Meixoeiro), Instituto de Investigación Sanitaria Galicia Sur (IISGS), Vigo, Pontevedra, Spain
| | - Maximiliano Álvarez-Fernández
- Servicio de Microbiología, Complejo Hospitalario Universitario de Vigo (Hospitales Álvaro Cunqueiro y Meixoeiro), Instituto de Investigación Sanitaria Galicia Sur (IISGS), Vigo, Pontevedra, Spain.
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21
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Contreras-Omaña R, Escorcia-Saucedo AE, Velarde-Ruiz Velasco JA. Prevalence and impact of antimicrobial resistance in gastrointestinal infections: A review. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2021; 86:265-275. [PMID: 34158260 DOI: 10.1016/j.rgmxen.2021.06.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 02/05/2021] [Indexed: 02/07/2023]
Abstract
Antimicrobial resistance has become a worldwide problem due to its excessive increase in recent years. The aim of the present review was to bring together data from different articles describing the levels of antimicrobial resistance in the most common gastrointestinal infections reported across the globe. The literature search was carried out in Google Scholar, Medline, Embase, and Pubmed, with the terms "antimicrobial resistance", "resistance in gastrointestinal disorders", and "resistance in amoebiasis", in Spanish and English. Mexican treatment guidelines and consensuses from 2017 to the present were utilized. Publications from the last ten years were chosen to describe the level of resistance. They had adequate sample sizes, the Material and Methods sections were precise, and they included multicenter studies, national and international consensuses, meta-analyses, systematic reviews, and extensive texts. The final number of articles was 51. The microorganisms that demonstrated the highest percentage of resistance were Helicobacter pylori (metronidazole 50%-80%, clarithromycin 20%-40%, and levofloxacin 30%-35%), Clostridioides difficile (clindamycin 8.3%-100%, cephalosporines 51%), Campylobacter jejuni and Campylobacter coli (fluoroquinolones 85%), Escherichia coli (ampicillin 76.5%), Entamoeba histolytica (metronidazole 50%), and bacterial peritonitis (third-generation cephalosporines 40%, methicillin 85%). Antimicrobial resistance is reaching elevated percentages, making it necessary to evaluate the situation of each patient, to successfully treat gastrointestinal infections.
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Affiliation(s)
- R Contreras-Omaña
- Centro de Investigación en Enfermedades Hepáticas y Gastroenterología (CIEHG), Pachuca, Hidalgo, Mexico.
| | - A E Escorcia-Saucedo
- Escuela de Medicina, Universidad Autónoma del Estado de Hidalgo, Hidalgo, Mexico
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22
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Kim JJE, Kocsmár I, Buzás GM, Szirtes I, Rusz O, Diczházi C, Szijártó A, Hritz I, Schaff Z, Kiss A, Kocsmár É, Lotz G. Efficacy of Clarithromycin Depends on the Bacterial Density in Clarithromycin-Heteroresistant Helicobacter pylori Infections: An In Situ Detected Susceptibility and Quantitative Morphometry-Based Retrospective Study. Pathol Oncol Res 2021; 27:1609863. [PMID: 34267605 PMCID: PMC8275651 DOI: 10.3389/pore.2021.1609863] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 06/16/2021] [Indexed: 01/06/2023]
Abstract
The global rise in clarithromycin (Cla) resistance is considered to be the main contributor of Helicobacter pylori (Hp) eradication failures. In nearly half of the Cla-resistant Hp infections, Cla-susceptible bacteria are simultaneously present with the Cla-resistant ones (Cla-heteroresistance). The proportion of resistant bacteria in the bacterial population (R-fraction) and its predictive role for the use of Cla-based therapies in Cla-heteroresistant infections has not yet been investigated. Our retrospective study analyzed gastric biopsy samples of 62 Hp-positive patients with Cla-heteroresistant infection. Fluorescence In Situ Hybridization technique was used to visualize the coexistence of resistant and susceptible bacteria within one tissue sample. R-fraction was quantified on multichannel microimages by digital morphometry. Resistant bacteria had a patchy distribution within the whole bacterial population causing high diversity among the investigated areas. Patients were subdivided into two major groups according to whether a Cla-based eradication attempt was conducted before or after the biopsy sampling. R-fraction was significantly lower among cases having only one previous Cla-based eradication attempt vs. those that had multiple previous eradications, including at least one Cla-containing therapy (0.41 vs. 0.89, p = 0.0308). Majority of the patients without previous eradication attempt had successful eradication with Cla-containing regimen (59.26%), verified by a negative 13C-urea breath test or control biopsy. Multivariable model indicated that the therapeutic outcome using Cla-based regimens depended on the bacterial density rather than the R-fraction. Our study raises the potential use of Cla-containing eradication therapies in certain Cla-heteroresistant Hp infections, taking into account the possible predictive role of bacterial density.
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Affiliation(s)
- Jewel Ju Ea Kim
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
| | - Ildikó Kocsmár
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
| | - György Miklós Buzás
- Department of Gastroenterology, Ferencváros Health Centre, Budapest, Hungary
| | - Ildikó Szirtes
- Department of Pharmacy, Péterfy Hospital - National Institute of Traumatology, Budapest, Hungary
| | - Orsolya Rusz
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary.,Department of Pharmacy, Péterfy Hospital - National Institute of Traumatology, Budapest, Hungary
| | - Csaba Diczházi
- Department of Pathology, Péterfy Hospital - National Institute of Traumatology, Budapest, Hungary
| | - Attila Szijártó
- 1st Department of Surgery and Interventional Gastroenterology, Semmelweis University, Budapest, Hungary
| | - István Hritz
- 1st Department of Surgery and Interventional Gastroenterology, Semmelweis University, Budapest, Hungary
| | - Zsuzsa Schaff
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
| | - András Kiss
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
| | - Éva Kocsmár
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
| | - Gábor Lotz
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
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23
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Moghadam MT, Chegini Z, Norouzi A, Dousari AS, Shariati A. Three-Decade Failure to the Eradication of Refractory Helicobacter pylori Infection and Recent Efforts to Eradicate the Infection. Curr Pharm Biotechnol 2021; 22:945-959. [PMID: 32767919 DOI: 10.2174/1389201021666200807110849] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 06/30/2020] [Accepted: 07/04/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Helicobacter pylori causes dangerous and deadly diseases such as gastric cancer and duodenal ulcers. Eradication and treatment of this bacterium are very important due to the deadly diseases caused by H. pylori and the high cost of treatment for countries. METHODS Thus, we present a complete list of the most important causes of failure in the treatment and eradication of H. pylori, and address new therapeutic methods that may be effective in controlling this bacterium in the future. RESULTS Many efforts have been made to control and eradicate this bacterium over the years, but no success has been achieved since its eradication is a complex process affected by the bacterial properties and host factors. Previous studies have shown that various factors are involved in the failure to eradicate H. pylori, such as new genotypes of the bacterium with higher pathogenicity, inappropriate patient cooperation, mutations, biofilm formation and dormant forms that cause antibiotic resistance, acidic stomach pH, high bacterial load, smoking, immunosuppressive features and intracellular occurrence of H. pylori. On the other hand, recent studies reported that the use of probiotics, nanoparticles, antimicrobial peptides, natural product and vaccines can be helpful in the treatment and eradication of H. pylori infections. CONCLUSION Eradication of H. pylori is crucial for the treatment of important diseases such as gastric cancer. Therefore, it seems that identifying the failure causes of treating this bacterium can be helpful in controlling the infections. Besides, further studies on new therapeutic strategies may help eradicate H. pylori in the future.
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Affiliation(s)
- Majid T Moghadam
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Chegini
- Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
| | - Amin Norouzi
- Department of Microbiology and Virology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | | | - Aref Shariati
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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24
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Mi M, Wu F, Zhu J, Liu F, Cui G, Wen X, Hu Y, Deng Z, Wu X, Zhang Z, Qi T, Chen Z. Heterogeneity of Helicobacter pylori Strains Isolated from Patients with Gastric Disorders in Guiyang, China. Infect Drug Resist 2021; 14:535-545. [PMID: 33603417 PMCID: PMC7886087 DOI: 10.2147/idr.s287631] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 01/09/2021] [Indexed: 12/17/2022] Open
Abstract
Purpose Chronic Helicobacter pylori infection causes peptic ulcers in a subpopulation of individuals and is a risk factor for the development of gastric cancer. Multiple infections and heteroresistant H. pylori contribute to poor treatment efficacy. Here, we investigated the extent of genetic diversity among H. pylori strains within a given host and its influence on the results of antibiotic (metronidazole, levofloxacin, clarithromycin, amoxicillin, and tetracycline) susceptibility testing. Materials and Methods Gastric mucosa biopsy samples were obtained from patients with gastric disorders, including 48 H. pylori positive patients, who were never previously treated for H. pylori infection. Five potential H. pylori colonies isolated from each sample were subcultured for enrichment. Enriched H. pylori colonies were identified through Gram staining and assays for urease, oxidase, and catalase. For each H. pylori monoclonal colony, the antibiotic susceptibility was assessed, genomic DNA was sequenced, and the cytotoxin-associated gene A (cagA) genotype was verified. Co-infection with multiple H. pylori strains was determined using random amplified polymorphic DNA (RAPD)-polymerase chain reaction (PCR). Results Thirteen gastric mucosa biopsy samples were positive for H. pylori. Five monoclonal strains isolated from each of these 13 patients were identified as H. pylori. RAPD-PCR indicated that intra-patient monoclonal strains of H. pylori in 10 of the 13 samples exhibited heterogeneity. Among the 13 patients, intra-patient monoclonal strains isolated from 4 patients had identical cagA genotype, whereas intra-patient monoclonal strains isolated from the other 9 patients harbored more than one cagA genotype. The antibiotic susceptibility of five intra-patient monoclonal strains from seven patients was inconsistent. Conclusion The existence of heterogeneous H. pylori strains with resistance to different drugs and virulence were common within the gastric mucosa of an individual patient.
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Affiliation(s)
- Mengheng Mi
- Key Laboratory of Microbiology and Parasitology of Education Department of Guizhou, School of Basic Medical Science, Guizhou Medical University/Joint Laboratory of Helicobacter Pylori and Intestinal Microecology of Affiliated Hospital of Guizhou Medical University, Guiyang, People's Republic of China.,Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, People's Republic of China
| | - Fangcao Wu
- Key Laboratory of Microbiology and Parasitology of Education Department of Guizhou, School of Basic Medical Science, Guizhou Medical University/Joint Laboratory of Helicobacter Pylori and Intestinal Microecology of Affiliated Hospital of Guizhou Medical University, Guiyang, People's Republic of China.,Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, People's Republic of China
| | - Jian Zhu
- Department of Gastroenterology, Guiyang Hospital of Guizhou Aviation Industry Group, Guiyang, People's Republic of China
| | - Fang Liu
- Key Laboratory of Microbiology and Parasitology of Education Department of Guizhou, School of Basic Medical Science, Guizhou Medical University/Joint Laboratory of Helicobacter Pylori and Intestinal Microecology of Affiliated Hospital of Guizhou Medical University, Guiyang, People's Republic of China.,Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, People's Republic of China
| | - Guzhen Cui
- Key Laboratory of Microbiology and Parasitology of Education Department of Guizhou, School of Basic Medical Science, Guizhou Medical University/Joint Laboratory of Helicobacter Pylori and Intestinal Microecology of Affiliated Hospital of Guizhou Medical University, Guiyang, People's Republic of China.,Key Laboratory of Endemic and Ethnic Diseases (Guizhou Medical University), Ministry of Education, Guiyang, People's Republic of China
| | - Xueqing Wen
- Key Laboratory of Microbiology and Parasitology of Education Department of Guizhou, School of Basic Medical Science, Guizhou Medical University/Joint Laboratory of Helicobacter Pylori and Intestinal Microecology of Affiliated Hospital of Guizhou Medical University, Guiyang, People's Republic of China.,Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, People's Republic of China
| | - Yue Hu
- Department of Gastroenterology, Affiliated Hospital of Guizhou Medical University, Guiyang, People's Republic of China
| | - Zhaohui Deng
- Department of Gastroenterology, Guiyang Hospital of Guizhou Aviation Industry Group, Guiyang, People's Republic of China
| | - Xiaojuan Wu
- Key Laboratory of Microbiology and Parasitology of Education Department of Guizhou, School of Basic Medical Science, Guizhou Medical University/Joint Laboratory of Helicobacter Pylori and Intestinal Microecology of Affiliated Hospital of Guizhou Medical University, Guiyang, People's Republic of China.,Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, People's Republic of China
| | - Zhengrong Zhang
- Key Laboratory of Microbiology and Parasitology of Education Department of Guizhou, School of Basic Medical Science, Guizhou Medical University/Joint Laboratory of Helicobacter Pylori and Intestinal Microecology of Affiliated Hospital of Guizhou Medical University, Guiyang, People's Republic of China.,Key Laboratory of Endemic and Ethnic Diseases (Guizhou Medical University), Ministry of Education, Guiyang, People's Republic of China
| | - Tingna Qi
- Key Laboratory of Microbiology and Parasitology of Education Department of Guizhou, School of Basic Medical Science, Guizhou Medical University/Joint Laboratory of Helicobacter Pylori and Intestinal Microecology of Affiliated Hospital of Guizhou Medical University, Guiyang, People's Republic of China.,Key Laboratory of Endemic and Ethnic Diseases (Guizhou Medical University), Ministry of Education, Guiyang, People's Republic of China
| | - Zhenghong Chen
- Key Laboratory of Microbiology and Parasitology of Education Department of Guizhou, School of Basic Medical Science, Guizhou Medical University/Joint Laboratory of Helicobacter Pylori and Intestinal Microecology of Affiliated Hospital of Guizhou Medical University, Guiyang, People's Republic of China.,Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, People's Republic of China
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25
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Gisbert JP. Rifabutin for the Treatment of Helicobacter Pylori Infection: A Review. Pathogens 2020; 10:pathogens10010015. [PMID: 33379336 PMCID: PMC7823349 DOI: 10.3390/pathogens10010015] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 12/17/2020] [Accepted: 12/24/2020] [Indexed: 12/12/2022] Open
Abstract
Nowadays, apart from having to know first-line Helicobacter pylori eradication regimens well, we must also be prepared to face treatment failures. The aim of this review is to summarize the role of rifabutin in the management of H. pylori infection. Bibliographical searches were performed in PubMed. Data on resistance and efficacy of rifabutin-containing regimens on H. pylori eradication were meta-analyzed. Mean H. pylori rifabutin resistance rate (39 studies, including 9721 patients) was 0.13%; when studies only including patients naïve to H. pylori eradication treatment were considered, this figure was even lower (0.07%). Mean H. pylori eradication rate (by intention-to-treat) with rifabutin-containing regimens (3052 patients) was 73%. Respective cure rates for second-, third-, fourth- and fifth-line therapies, were 79%, 69%, 69% and 72%. Most studies administered rifabutin 300 mg/day, which seemed to be more effective than 150 mg/day. The ideal length of treatment remains unclear, but 10–12-day regimens are generally recommended. Adverse events to rifabutin treatment in H. pylori studies were relatively infrequent (15%), and severe adverse events were exceptional (myelotoxicity was the most significant, although always reversible). In summary, rifabutin-containing therapy represents an encouraging strategy generally restricted, at present, to patients where previous (usually multiple) eradication regimens have failed.
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Affiliation(s)
- Javier P Gisbert
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid (UAM), and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28006 Madrid, Spain
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26
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Moreno-Flores A, Potel-Alvarellos C, Álvarez-Fernández M. Helicobacter pylori, antimicrobial resistance evolution 2012-2020 in Vigo sanitary area, Pontevedra, Spain. Enferm Infecc Microbiol Clin 2020; 39:S0213-005X(20)30403-1. [PMID: 33358497 DOI: 10.1016/j.eimc.2020.10.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 10/26/2020] [Accepted: 10/31/2020] [Indexed: 11/25/2022]
Affiliation(s)
- Antonio Moreno-Flores
- Servicio de Microbiología, Complejo Hospitalario Universitario de Vigo (Hospitales Álvaro Cunqueiro y Meixoeiro). Instituto de Investigación Sanitaria Galicia Sur (IISGS), Vigo, Pontevedra, España
| | - Carmen Potel-Alvarellos
- Servicio de Microbiología, Complejo Hospitalario Universitario de Vigo (Hospitales Álvaro Cunqueiro y Meixoeiro). Instituto de Investigación Sanitaria Galicia Sur (IISGS), Vigo, Pontevedra, España
| | - Maximiliano Álvarez-Fernández
- Servicio de Microbiología, Complejo Hospitalario Universitario de Vigo (Hospitales Álvaro Cunqueiro y Meixoeiro). Instituto de Investigación Sanitaria Galicia Sur (IISGS), Vigo, Pontevedra, España.
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27
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Zhou JJ, Shi X, Zheng SP, Tang D, Cai T, Yao Y, Wang F. Efficacy of bismuth-based quadruple therapy for eradication of Helicobacter pylori infection based on previous antibiotic exposure: A large-scale prospective, single-center clinical trial in China. Helicobacter 2020; 25:e12755. [PMID: 32914914 DOI: 10.1111/hel.12755] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 07/29/2020] [Accepted: 08/06/2020] [Indexed: 01/30/2023]
Abstract
OBJECTIVE This study aims to evaluate the efficacy and safety of three bismuth-based quadruple regimens for eradication of Helicobacter pylori (H pylori) infection in a large number of H pylori-positive patients with or without previous eradication therapy. METHODS Consecutive adult patients with H pylori infection, regardless of previous eradication therapy, were eligible for the present study. Three bismuth-based quadruple regimens were selected according to the past history of antibiotics use: (A) esomeprazole, amoxicillin, clarithromycin, and colloidal bismuth tartrate; (B) esomeprazole, amoxicillin, furazolidone, and colloidal bismuth tartrate; and (C) esomeprazole, doxycycline, furazolidone, and colloidal bismuth tartrate. All patients received a 14-day course of treatment, and 13 C/14 C urea breath test was utilized at four weeks after the completion of treatment to determine the H pylori eradication. Then, the eradication rates were calculated in terms of intention-to-treat (ITT) and per-protocol (PP) analyses. Adverse events (AEs) were recorded during the treatment. RESULTS Overall, 1,226 patients were recruited, and 331, 57, and 838 patients were allocated to receive regimens A, B, and C, respectively. The H pylori eradication rates were 84.0%, 82.5%, and 82.9% (ITT) and 94.6%, 92.2%, and 93.7% (PP), respectively, in regimens A, B, and C. However, there was no significant difference among these three regimens. The incidence of AEs was 4.6% for all patients during the study, that is, 3.3%, 10.5%, and 4.7% for regimens A, B, and C, respectively. All AEs were mild and recovered at the follow-up visit. CONCLUSION All three bismuth-based quadruple regimens based on the previous antibiotic use can achieve satisfactory eradication rates for H pylori infection and are safe.
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Affiliation(s)
- Jing-Jing Zhou
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Non-Resolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Xiao Shi
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Non-Resolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Shao-Peng Zheng
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Non-Resolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Dan Tang
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Non-Resolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Ting Cai
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Non-Resolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Yao Yao
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Non-Resolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Fen Wang
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Non-Resolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, China
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28
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Fisher L, Fisher A, Smith PN. Helicobacter pylori Related Diseases and Osteoporotic Fractures (Narrative Review). J Clin Med 2020; 9:E3253. [PMID: 33053671 PMCID: PMC7600664 DOI: 10.3390/jcm9103253] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 09/28/2020] [Accepted: 10/07/2020] [Indexed: 02/06/2023] Open
Abstract
Osteoporosis (OP) and osteoporotic fractures (OFs) are common multifactorial and heterogenic disorders of increasing incidence. Helicobacter pylori (H.p.) colonizes the stomach approximately in half of the world's population, causes gastroduodenal diseases and is prevalent in numerous extra-digestive diseases known to be associated with OP/OF. The studies regarding relationship between H.p. infection (HPI) and OP/OFs are inconsistent. The current review summarizes the relevant literature on the potential role of HPI in OP, falls and OFs and highlights the reasons for controversies in the publications. In the first section, after a brief overview of HPI biological features, we analyze the studies evaluating the association of HPI and bone status. The second part includes data on the prevalence of OP/OFs in HPI-induced gastroduodenal diseases (peptic ulcer, chronic/atrophic gastritis and cancer) and the effects of acid-suppressive drugs. In the next section, we discuss the possible contribution of HPI-associated extra-digestive diseases and medications to OP/OF, focusing on conditions affecting both bone homeostasis and predisposing to falls. In the last section, we describe clinical implications of accumulated data on HPI as a co-factor of OP/OF and present a feasible five-step algorithm for OP/OF risk assessment and management in regard to HPI, emphasizing the importance of an integrative (but differentiated) holistic approach. Increased awareness about the consequences of HPI linked to OP/OF can aid early detection and management. Further research on the HPI-OP/OF relationship is needed to close current knowledge gaps and improve clinical management of both OP/OF and HPI-related disorders.
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Affiliation(s)
- Leon Fisher
- Department of Gastroenterology, Frankston Hospital, Peninsula Health, Melbourne 3199, Australia
| | - Alexander Fisher
- Department of Geriatric Medicine, The Canberra Hospital, ACT Health, Canberra 2605, Australia;
- Department of Orthopedic Surgery, The Canberra Hospital, ACT Health, Canberra 2605, Australia;
- Australian National University Medical School, Canberra 2605, Australia
| | - Paul N Smith
- Department of Orthopedic Surgery, The Canberra Hospital, ACT Health, Canberra 2605, Australia;
- Australian National University Medical School, Canberra 2605, Australia
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29
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Ji CR, Liu J, Li YY, Qiao C, Qu JY, Hu JN, Lin MJ, Ji R, Li LX, Zuo XL, Li YQ. Susceptibility-guided quadruple therapy is not superior to medication history-guided therapy for the rescue treatment of Helicobacter pylori infection: A randomized controlled trial. J Dig Dis 2020; 21:549-557. [PMID: 32833285 DOI: 10.1111/1751-2980.12934] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 07/14/2020] [Accepted: 08/05/2020] [Indexed: 12/11/2022]
Abstract
OBJECTIVE In this study we aimed to compare the efficacy and safety of two personalized rescue therapies for Helicobacter pylori infection. METHODS An open-label, single-center, randomized controlled trial was conducted. Patients who had failed one or two regimens for H. pylori infection were randomized to receive a 14-day bismuth-containing quadruple therapy guided by antimicrobial susceptibility testing (AST) or personal medication history (PMH). In the AST group, either two of amoxicillin, clarithromycin, metronidazole or levofloxacin were prescribed according to the AST. In the PMH group, amoxicillin plus either levofloxacin or furazolidone were prescribed based on the patient's history of quinolone use. The primary outcomes were eradication rates confirmed by an urea breath test 6 weeks after treatment. The secondary outcomes were adherence, incidence of adverse events (AE) and cost-effectiveness. RESULTS Altogether 164 with a positive culture received AST-guided therapy and 192 received PMH-guided therapy, respectively. Both AST- and PMH-guided therapies achieved comparable eradication rate (intention-to-treat analysis: 78.10% vs 74.29%, P = 0.42; per-protocol analysis: 87.10% vs 88.64%, P = 0.80). The AST clarithromycin regimen had a lower per-protocol eradication rate than the levofloxacin (75.47% vs 96.30%, P = 0.03) or furazolidone-containing regimen (75.47% vs 92.75%, P = 0.02). Both groups had high compliance with low incidences of AE, and PMH-guided therapy had a lower medical cost. CONCLUSIONS AST-guided therapy was not superior to PMH-guided therapy as a second- or third-line treatment for H. pylori infection. Considering the cost-effectiveness, PMH therapy is clinically more favorable.
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Affiliation(s)
- Chao Ran Ji
- Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China.,Laboratory of Translational Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Jing Liu
- Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China.,Laboratory of Translational Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Yue Yue Li
- Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China.,Laboratory of Translational Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Chen Qiao
- Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China.,Laboratory of Translational Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Jun Yan Qu
- Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China.,Laboratory of Translational Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Jun Nan Hu
- Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China.,Laboratory of Translational Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Min Juan Lin
- Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China.,Laboratory of Translational Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Rui Ji
- Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China.,Laboratory of Translational Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Li Xiang Li
- Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China.,Laboratory of Translational Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Xiu Li Zuo
- Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China.,Laboratory of Translational Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Yan Qing Li
- Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China.,Laboratory of Translational Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
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30
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Where to Biopsy to Detect Helicobacter pylori and How Many Biopsies Are Needed to Detect Antibiotic Resistance in a Human Stomach. J Clin Med 2020; 9:jcm9092812. [PMID: 32878081 PMCID: PMC7565078 DOI: 10.3390/jcm9092812] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 08/18/2020] [Accepted: 08/26/2020] [Indexed: 12/20/2022] Open
Abstract
This study aims to determine the gastric distribution, density, and diversity of Helicobacter pylori infection. Subtotal resection of the stomachs of three H. pylori-infected and asymptomatic obese patients were collected after a sleeve gastrectomy. Distribution and density of H. pylori were determined using culture and RT-PCR on multiple gastric sites (88, 176, and 101 biopsies per patient). Diversity of H. pylori strains was studied using antibiotic susceptibility testing, random amplified polymorphism DNA (RAPD) typing and cagA gene detection on single-colony isolates (44, 96, and 49 isolates per patient). H. pylori was detected in nearly all analyzed sites (354/365 biopsies, 97%). Antral density was higher in one patient only. The three stomachs were almost exclusively infected by an antibiotic-susceptible strain. One clarithromycin-resistant isolate in one biopsy was detected in two stomachs (1/44 and 1/49 isolates), while in the third one, eight (8/96 isolates) metronidazole-resistant isolates were detected. DNA typing showed infection with cagA-negative strains for one patient, cagA-positive strains for a second patient and the third patient was infected with two different strains of distinct cagA genotypes. Infection with H. pylori is shown to spread to the whole surface of the stomach, but a possibility of minor sub-population of antibiotic-resistant clones, undetectable in routine practice.
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Khien VV, Thang DM, Hai TM, Duat NQ, Khanh PH, Ha DT, Binh TT, Dung HDQ, Trang TTH, Yamaoka Y. Management of Antibiotic-Resistant Helicobacter pylori Infection: Perspectives from Vietnam. Gut Liver 2020; 13:483-497. [PMID: 31009957 PMCID: PMC6743798 DOI: 10.5009/gnl18137] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 11/13/2018] [Accepted: 11/27/2018] [Indexed: 12/15/2022] Open
Abstract
Antibiotic resistance is the most important factor leading to the failure of eradication regimens. This review focuses on the prevalence of Helicobacter pylori primary and secondary resistance to clarithromycin, metronidazole, amoxicillin, levofloxacin, tetracycline, and multidrug in Vietnam. We searched the PubMed, EMBASE, Vietnamese National Knowledge Infrastructure, and Vietnamese Biomedical databases from January 2000 to December 2016. The search terms included the following: H. pylori infection, antibiotic (including clarithromycin, metronidazole, amoxicillin, levofloxacin, tetracycline, and multidrug) resistance in Vietnam. The data were summarized in an extraction table and analyzed manually. Finally, Excel 2007 software was used to create charts. Ten studies (three studies in English and seven in Vietnamese) were included in this review. A total of 308, 412, 523, 408, 399, and 268 H. pylori strains were included in this review to evaluate the prevalence of H. pylori primary resistance to amoxicillin, clarithromycin, metronidazole, levofloxacin, tetracycline, and multidrug resistance, respectively. Overall, the primary resistance rates of amoxicillin, clarithromycin, metronidazole, levofloxacin, tetracycline, and multidrug resistance were 15.0%, 34.1%, 69.4%, 27.9%, 17.9% and 48.8%, respectively. Secondary resistance rates of amoxicillin, clarithromycin, metronidazole, levofloxacin, tetracycline, and multidrug resistance were 9.5%, 74.9%, 61.5%, 45.7%, 23.5% and 62.3%, respectively. In Vietnam, primary and secondary resistance to H. pylori is increasing over time and affects the effectiveness of H. pylori eradication.
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Affiliation(s)
- Vu Van Khien
- Departments of GI Endoscopy, 108 Central Hospital, Hanoi, Vietnam
| | - Duong Minh Thang
- Departments of GI Endoscopy, 108 Central Hospital, Hanoi, Vietnam
| | - Tran Manh Hai
- Departments of Molecular Biology, 108 Central Hospital, Hanoi, Vietnam.,University of Science and Technology of Hanoi, Hanoi, Vietnam
| | | | - Pham Hong Khanh
- Department of Gastroenterology, 103 Hospital, Hanoi, Vietnam
| | - Dang Thuy Ha
- Department of Gastroenterology, National Children Hospital, Hanoi, Vietnam
| | - Tran Thanh Binh
- Department of Endoscopy, Cho Ray Hospital, Ho Chi Minh City, Vietnam
| | - Ho Dang Quy Dung
- Department of Endoscopy, Cho Ray Hospital, Ho Chi Minh City, Vietnam
| | | | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Oita, Japan
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Kocsmár É, Kocsmár I, Buzás GM, Szirtes I, Wacha J, Takáts A, Hritz I, Schaff Z, Rugge M, Fassan M, Kiss A, Lotz G. Helicobacter pylori heteroresistance to clarithromycin in adults-New data by in situ detection and improved concept. Helicobacter 2020; 25:e12670. [PMID: 31701608 DOI: 10.1111/hel.12670] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Revised: 09/16/2019] [Accepted: 10/07/2019] [Indexed: 01/06/2023]
Abstract
BACKGROUND Clarithromycin (Cla) heteroresistance of Helicobacter pylori (H pylori) infections is commonly assessed by comparing the resistance status of antrum and corpus biopsy samples and by demonstrating the discrepancy between them (interniche heteroresistance). However, fluorescence in situ hybridization (FISH) technique is capable of showing the synchronous presence of susceptible and resistant bacteria (intraniche heteroresistance), enabling the detection of heteroresistant H pylori populations within one biopsy sample. MATERIALS AND METHODS Antrum and corpus biopsy specimens of 305 H pylori-infected patients were investigated with an rRNA-targeted Cla-resistance FISH test. Anamnestic data were collected from the institutional electronic register. Prevalence rates of susceptible, homo- and heteroresistant cases were correlated with the anamnestic and clinicopathological data. RESULTS Overall Cla-resistance rate was 23.9% (73 cases), consisting of 35 (11.5%) homoresistant and 38 (12.5%) heteroresistant cases. Thirty-five patients had at least one biopsy site where susceptible and resistant bacteria were present simultaneously. From this subset, 20 cases demonstrated intraniche heteroresistance on both sites. Prior Cla-based eradication attempts were more frequent in homoresistant than in susceptible and heteroresistant cases (P < .001, P < .001, respectively). Cla-containing therapy eradicated heteroresistant infections at a significantly lower rate in comparison with susceptible cases (P = .0112), but more effectively than homoresistants (P = .0393). CONCLUSIONS The most frequent type of Cla-heteroresistance is the coexistence of susceptible and resistant H pylori bacteria in the same location (intraniche heteroresistance). A previous Cla-based eradication attempt predisposes patients to homoresistant infection. Heteroresistance is characterized by a non-eradication-related background and intermediate characteristics in many respects when compared to susceptible and homoresistant cases.
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Affiliation(s)
- Éva Kocsmár
- Second Department of Pathology, Semmelweis University, Budapest, Hungary
| | - Ildikó Kocsmár
- Second Department of Pathology, Semmelweis University, Budapest, Hungary
| | - György Miklós Buzás
- Department of Gastroenterology, Ferencváros Health Centre, Budapest, Hungary
| | - Ildikó Szirtes
- Second Department of Pathology, Semmelweis University, Budapest, Hungary
| | - Judit Wacha
- First Department of Surgery, Semmelweis University, Budapest, Hungary
| | - Alajos Takáts
- First Department of Surgery, Semmelweis University, Budapest, Hungary
| | - István Hritz
- First Department of Surgery, Semmelweis University, Budapest, Hungary
| | - Zsuzsa Schaff
- Second Department of Pathology, Semmelweis University, Budapest, Hungary
| | - Massimo Rugge
- Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy.,Veneto Tumor Registry (RTV), Veneto Regional Authority, Padova, Italy
| | - Matteo Fassan
- Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - András Kiss
- Second Department of Pathology, Semmelweis University, Budapest, Hungary
| | - Gábor Lotz
- Second Department of Pathology, Semmelweis University, Budapest, Hungary
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Kotilea K, Bontems P, Touati E. Epidemiology, Diagnosis and Risk Factors of Helicobacter pylori Infection. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1149:17-33. [PMID: 31016621 DOI: 10.1007/5584_2019_357] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Helicobacter pylori is a human-specific pathogen, which leads to gastric pathologies including gastric cancer. It is a highly unique bacterium considered as a carcinogenic agent. H. pylori remains a major human health problem, responsible for ~90% of the gastric cancer cases. Approximately four billion individuals have been detected for H. pylori infection worldwide in 2015. At the turn of the twenty-first century, the prevalence of H. pylori has been declining in highly industrialized countries of the Western world, whereas prevalence has plateaued at a high level in developing and newly industrialized countries. However, the infection status remains high in immigrants coming from countries with high prevalence of H. pylori infection. H. pylori can be diagnosed both by invasive and non-invasive methods. Urea breath test and stool antigens detection are among the most commonly used non-invasive ones. Although the way H. pylori is transmitted remains still not fully clear, the level of contamination is strongly dependent on the familial and environmental context, with a drastic impact of living conditions with poor hygiene and sanitation. However, familial socioeconomic status is the main risk factor for H. pylori infection among children. In addition, food and water source have a high impact on the prevalence of H. pylori infection worldwide. This chapter highlights the latest knowledge in the epidemiology of H. pylori infection, its diagnosis and critical risk factors responsible for its high prevalence in some populations and geographic areas.
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Affiliation(s)
- Kallirroi Kotilea
- Paediatric Gastroenterology Unit, Université Libre de Bruxelles, Hôpital Universitaire des Enfants Reine Fabiola, Bruxelles, Belgium
| | - Patrick Bontems
- Paediatric Gastroenterology Unit, Université Libre de Bruxelles, Hôpital Universitaire des Enfants Reine Fabiola, Bruxelles, Belgium
| | - Eliette Touati
- Unit of Helicobacter Pathogenesis, Institut Pasteur, Paris, France.
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Vasapolli R, Schütte K, Schulz C, Vital M, Schomburg D, Pieper DH, Vilchez-Vargas R, Malfertheiner P. Analysis of Transcriptionally Active Bacteria Throughout the Gastrointestinal Tract of Healthy Individuals. Gastroenterology 2019; 157:1081-1092.e3. [PMID: 31175864 DOI: 10.1053/j.gastro.2019.05.068] [Citation(s) in RCA: 97] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Revised: 05/26/2019] [Accepted: 05/30/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS The microbiome varies along the human gastrointestinal (GI) tract with exposure to luminal and mucosal factors. We analyzed active bacterial communities at 8 locations along the GI tract using high-throughput sequencing techniques. METHODS We collected saliva, mucosal, and fecal samples from healthy adults (10 men and 11 women; mean age, 59 ± 12.3 years) who underwent upper and lower GI tract endoscopy in Germany from December 2015 through September 2016. Biopsies were taken from stomach, antrum, corpus, duodenum, terminal ileum, ascending colon, and descending colon. RNA was extracted from all samples and reverse transcribed into complementary DNA; V1-V2 regions of 16S ribosomal RNA genes were amplified and sequenced on an Illumina MiSeq platform. Abundances of the taxa in all taxonomic ranks in each sample type were used to construct sample-similarity matrices with the Bray-Curtis algorithm. Significant differences between a priori-defined groups were evaluated using analysis of similarity. RESULTS After taxonomic annotation, 4045 phylotypes, belonging to 169 genera and 14 different phyla, were identified. Each subject had a different bacterial community. We identified distinct microbial consortia in saliva, upper GI tract, lower GI tract, and fecal samples. The predominant genera in the upper GI tract (Gemella, Veillonella, Neisseria, Fusobacterium, Streptococcus, Prevotella, Pseudomonas, and Actinomyces) were almost absent from the lower GI tract, where the microbial communities mainly comprised Faecalibacterium, Ruminococcus, and Bacteroides. The bacterial communities in the upper GI tract were characterized by greater richness and heterogeneity (measured by the Shannon index) than those in the lower GI tract. We detected Helicobacter pylori in only the upper GI tract. CONCLUSIONS In an analysis of saliva, mucosal, and fecal samples from 21 healthy adults, we found each individual, and each GI region, to have a different bacterial community. The fecal microbiome is not representative of the mucosal microbiome. We propose a systematic method to analyze the bacterial communities of the GI tract.
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Affiliation(s)
- Riccardo Vasapolli
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke-University of Magdeburg, Magdeburg, Germany; Department of Internal Medicine II, Hospital of the Ludwig Maximilians University of Munich, Munich, Germany
| | - Kerstin Schütte
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke-University of Magdeburg, Magdeburg, Germany; Department of Internal Medicine and Gastroenterology, Niels-Stensen-Kliniken, Marienhospital, Osnabrück, Germany
| | - Christian Schulz
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke-University of Magdeburg, Magdeburg, Germany; Department of Internal Medicine II, Hospital of the Ludwig Maximilians University of Munich, Munich, Germany
| | - Marius Vital
- Microbial Interactions and Processes Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany; Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
| | - Dirk Schomburg
- Department for Biometrics and Medical Informatics, Otto-von-Guericke-University of Magdeburg, Magdeburg, Germany
| | - Dietmar H Pieper
- Microbial Interactions and Processes Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Ramiro Vilchez-Vargas
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke-University of Magdeburg, Magdeburg, Germany
| | - Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke-University of Magdeburg, Magdeburg, Germany; Department of Internal Medicine II, Hospital of the Ludwig Maximilians University of Munich, Munich, Germany.
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Hanafiah A, Binmaeil H, Raja Ali RA, Mohamed Rose I, Lopes BS. Molecular characterization and prevalence of antibiotic resistance in Helicobacter pylori isolates in Kuala Lumpur, Malaysia. Infect Drug Resist 2019; 12:3051-3061. [PMID: 31632095 PMCID: PMC6774992 DOI: 10.2147/idr.s219069] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 07/25/2019] [Indexed: 12/12/2022] Open
Abstract
Aims and objectives Helicobacter pylori has been classified as high priority pathogen by the WHO in 2017. The emergence of antibiotic-resistant strains is one of the main causes of treatment failure in H. pylori infection. This study determined and characterized primary and secondary resistances in H. pylori in Malaysia. Materials and methods Gastric biopsies from antrum (n=288) and corpus (n=283) were obtained from 288 patients who underwent endoscopy at Universiti Kebangsaan Malaysia Medical Center (UKMMC), Kuala Lumpur, Malaysia. Antibiotic susceptibility to six classes of antibiotics was determined by the E-test. Mutations conferring in resistance in functional genes were identified by PCR and sequencing. Results Overall resistance rates to metronidazole, clarithromycin and levofloxacin were 59.3% (35/59), 35.6% (21/59) and 25.4% (15/59), respectively. Secondary isolates showed significantly higher resistance rates to clarithromycin compared to the primary isolates. Mixed infection with susceptible and resistant isolates was observed in 16.2% (6/37) of cases, of which 83.3% (n=5) had infection with the same strain. 41% (18/44) of isolates were resistant to more than one class of antibiotics of which 50% (9/18) were multidrug-resistant, two being primary and seven being secondary isolates. Mutations in rdxA, 23S rRNA and gyrA genes were associated with resistance to metronidazole, clarithromycin and levofloxacin, respectively. Conclusion The high level of resistance to metronidazole, clarithromycin and levofloxacin seen in H. pylori isolates in our setting warrants the need for continuous surveillance and highlights caution in use of antibiotics generally used as first-line therapy in H. pylori eradication regimen.
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Affiliation(s)
| | | | | | - Isa Mohamed Rose
- Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia
| | - Bruno S Lopes
- Department of Medical Microbiology, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK
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Pohl D, Keller PM, Bordier V, Wagner K. Review of current diagnostic methods and advances in Helicobacter pylori diagnostics in the era of next generation sequencing. World J Gastroenterol 2019; 25:4629-4660. [PMID: 31528091 PMCID: PMC6718044 DOI: 10.3748/wjg.v25.i32.4629] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 06/25/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) infection is highly prevalent in the human population and may lead to severe gastrointestinal pathology including gastric and duodenal ulcers, mucosa associated tissue lymphoma and gastric adenocarcinoma. In recent years, an alarming increase in antimicrobial resistance and subsequently failing empiric H. pylori eradication therapies have been noted worldwide, also in many European countries. Therefore, rapid and accurate determination of H. pylori’s antibiotic susceptibility prior to the administration of eradication regimens becomes ever more important. Traditionally, detection of H. pylori and its antimicrobial resistance is done by culture and phenotypic drug susceptibility testing that are cumbersome with a long turn-around-time. Recent advances in diagnostics provide new tools, like real-time polymerase chain reaction (PCR) and line probe assays, to diagnose H. pylori infection and antimicrobial resistance to certain antibiotics, directly from clinical specimens. Moreover, high-throughput whole genome sequencing technologies allow the rapid analysis of the pathogen’s genome, thereby allowing identification of resistance mutations and associated antibiotic resistance. In the first part of this review, we will give an overview on currently available diagnostic methods for detection of H. pylori and its drug resistance and their implementation in H. pylori management. The second part of the review focusses on the use of next generation sequencing technology in H. pylori research. To this end, we conducted a literature search for original research articles in English using the terms “Helicobacter”, “transcriptomic”, “transcriptome”, “next generation sequencing” and “whole genome sequencing”. This review is aimed to bridge the gap between current diagnostic practice (histology, rapid urease test, H. pylori culture, PCR and line probe assays) and new sequencing technologies and their potential implementation in diagnostic laboratory settings in order to complement the currently recommended H. pylori management guidelines and subsequently improve public health.
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Affiliation(s)
- Daniel Pohl
- Division of Gastroenterology, University Hospital of Zurich, Zurich 8006, Switzerland
| | - Peter M Keller
- Institute for Infectious Diseases, University of Bern, Bern 3010, Switzerland
| | - Valentine Bordier
- Division of Gastroenterology, University Hospital of Zurich, Zurich 8006, Switzerland
| | - Karoline Wagner
- Institute of Medical Microbiology, University of Zurich, Zurich 8006, Switzerland
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Seo JW, Park JY, Shin TS, Kim JG. The analysis of virulence factors and antibiotic resistance between Helicobacter pylori strains isolated from gastric antrum and body. BMC Gastroenterol 2019; 19:140. [PMID: 31390989 PMCID: PMC6686454 DOI: 10.1186/s12876-019-1062-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Accepted: 07/31/2019] [Indexed: 02/08/2023] Open
Abstract
Background Individuals can be infected with multiple strains of Helicobacter pylori. However, the differences among co-infecting strains have not been well analyzed yet. This study aimed to investigate whether the virulence factors and antibiotic resistance patterns of H. pylori differ between strains isolated from different locations of the stomach in the same patient. Methods H. pylori isolates were obtained from the antrum and body of the stomach. Genetic differences were examined by random amplified polymorphic DNA (RAPD) fingerprinting. Antibiotic resistance was assessed using the agar dilution method. Virulence factors were identified by polymerase chain reaction and DNA sequencing. Results Among 80 patients, co-infection by two H. pylori strains was detected in 10 patients. Among the 10 pairs of H. pylori strains, differences in antibiotic resistance patterns were detected in 7 pairs (clarithromycin, 1 patient; quinolone, 3 patients; metronidazole, 4 patients) and differences in virulence factors were detected in 5 pairs. The cagA virulence gene was detected in all 10 patients, and 2 patients had H. pylori strains with different EPIYA motifs. Differences in vacA genotypes were detected in 4 patients. Conclusions Co-infection by two H. pylori strains was confirmed by RAPD fingerprinting. Frequently, two H. pylori strains obtained from a single host differed in their virulence factors and antibiotic resistance patterns. Co-infection by multiple H. pylori strains could undermine the success of eradication therapy and should be considered when interpreting the results of antimicrobial susceptibility tests. Electronic supplementary material The online version of this article (10.1186/s12876-019-1062-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ji Won Seo
- Department of Biomedical Science, Chung-Ang University College of Medicine, Seoul, South Korea
| | - Jae Yong Park
- Department of Internal Medicine, Chung-Ang University Hospital, Seoul, South Korea
| | - Tae-Seop Shin
- Research Institute, Chung-Ang University, Seoul, South Korea
| | - Jae Gyu Kim
- Department of Internal Medicine, Chung-Ang University College of Medicine, 102 Heukseok-ro, Dongjak-gu, Seoul, 06973, Republic of Korea.
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Arévalo-Jaimes BV, Rojas-Rengifo DF, Jaramillo CA, de Molano BM, Vera-Chamorro JF, Del Pilar Delgado M. Genotypic determination of resistance and heteroresistance to clarithromycin in Helicobacter pylori isolates from antrum and corpus of Colombian symptomatic patients. BMC Infect Dis 2019; 19:546. [PMID: 31226948 PMCID: PMC6587245 DOI: 10.1186/s12879-019-4178-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 06/10/2019] [Indexed: 02/10/2023] Open
Abstract
BACKGROUND The effectiveness of Helicobacter pylori first-line treatment has decreased drastically with the rise of strains resistant to clarithromycin. Therapy failure has also been described in patients with infections by strains with dissimilar antimicrobial susceptibilities. The present study aims to estimate the prevalence of resistance and heteroresistance to clarithromycin in H. pylori isolates from antrum and corpus of Colombian patients. METHODS The study material included 126 isolates from antrum and corpus biopsies from 63 symptomatic patients over 18 years old who had a gastric endoscopy performed on them between June 2014 to August 2016. PCR amplification and sequencing of the H. pylori 23S rDNA gene was performed to determine the presence of mutations associated with clarithromycin resistance. Random amplified polymorphic DNA analysis was implemented in cases of resistance and heteroresistance. RESULTS The overall frequency of resistance to clarithromycin was 38.1% (24/63 patients), of which 19 patients had resistant isolates in both stomach segments (14 with A2143G mutation and 5 with A2142G mutation), and 5 patients had a heteroresistant status. The remaining 61.9% (39/63 patients) presented only susceptible isolates. DNA fingerprinting analysis showed different patterns in 4/22 paired isolates. CONCLUSIONS The high prevalence of H. pylori clarithromycin-resistance obtained (> 15%) constitutes an alert for gastroenterologists and suggests the need for reconsideration of the current eradication regimen for H. pylori in the studied population. The data show that heteroresistance status is an additional factor to be considered in the assessment of resistance. In consequence, it is advisable to examine at least two biopsies from different gastric segments.
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Affiliation(s)
- Betsy Verónica Arévalo-Jaimes
- Molecular Diagnostics and Bioinformatics Laboratory, Department of Biological Sciences, Los Andes University, Cra 1 # 18A- 10 Office J211, Zip Code, 111711, Bogotá, Colombia
| | - Diana F Rojas-Rengifo
- Molecular Diagnostics and Bioinformatics Laboratory, Department of Biological Sciences, Los Andes University, Cra 1 # 18A- 10 Office J211, Zip Code, 111711, Bogotá, Colombia
| | - Carlos Alberto Jaramillo
- Molecular Diagnostics and Bioinformatics Laboratory, Department of Biological Sciences, Los Andes University, Cra 1 # 18A- 10 Office J211, Zip Code, 111711, Bogotá, Colombia
| | - Belén Mendoza de Molano
- Gastroenterology Department, University Hospital Foundation Santa Fe de Bogotá, Bogotá, Colombia
| | | | - María Del Pilar Delgado
- Molecular Diagnostics and Bioinformatics Laboratory, Department of Biological Sciences, Los Andes University, Cra 1 # 18A- 10 Office J211, Zip Code, 111711, Bogotá, Colombia.
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Ailloud F, Didelot X, Woltemate S, Pfaffinger G, Overmann J, Bader RC, Schulz C, Malfertheiner P, Suerbaum S. Within-host evolution of Helicobacter pylori shaped by niche-specific adaptation, intragastric migrations and selective sweeps. Nat Commun 2019; 10:2273. [PMID: 31118420 PMCID: PMC6531487 DOI: 10.1038/s41467-019-10050-1] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 04/10/2019] [Indexed: 02/07/2023] Open
Abstract
The human pathogen Helicobacter pylori displays extensive genetic diversity. While H. pylori is known to evolve during infection, population dynamics inside the gastric environment have not been extensively investigated. Here we obtained gastric biopsies from multiple stomach regions of 16 H. pylori-infected adults, and analyze the genomes of 10 H. pylori isolates from each biopsy. Phylogenetic analyses suggest location-specific evolution and bacterial migration between gastric regions. Migration is significantly more frequent between the corpus and the fundus than with the antrum, suggesting that physiological differences between antral and oxyntic mucosa contribute to spatial partitioning of H. pylori populations. Associations between H. pylori gene polymorphisms and stomach niches suggest that chemotaxis, regulatory functions and outer membrane proteins contribute to specific adaptation to the antral and oxyntic mucosa. Moreover, we show that antibiotics can induce severe population bottlenecks and likely play a role in shaping the population structure of H. pylori.
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Affiliation(s)
- Florent Ailloud
- Department of Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer Institute, Faculty of Medicine, LMU Munich, 80336, Munich, Germany
- Institute of Medical Microbiology and Hospital Epidemiology, MHH Hannover Medical School, 30625, Hannover, Germany
- DZIF German Center for Infection Research, Munich Site, Munich, Germany
- DZIF German Center for Infection Research, Hannover-Braunschweig Site, Hannover, Germany
| | - Xavier Didelot
- School of Life Sciences, University of Warwick, Coventry, CV4 7AL, UK
- Department of Statistics, University of Warwick, Coventry, CV4 7AL, UK
| | - Sabrina Woltemate
- Institute of Medical Microbiology and Hospital Epidemiology, MHH Hannover Medical School, 30625, Hannover, Germany
| | - Gudrun Pfaffinger
- Department of Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer Institute, Faculty of Medicine, LMU Munich, 80336, Munich, Germany
| | - Jörg Overmann
- DZIF German Center for Infection Research, Hannover-Braunschweig Site, Hannover, Germany
- Leibniz Institute DSMZ - German Collection of Microorganisms and Cell Cultures, 38124, Braunschweig, Germany
| | - Ruth Christiane Bader
- Department of Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer Institute, Faculty of Medicine, LMU Munich, 80336, Munich, Germany
- National Reference Center for Helicobacter pylori, Max von Pettenkofer Institute, 80336, Munich, Germany
| | - Christian Schulz
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto von Guericke University, 39106, Magdeburg, Germany
- Department of Medicine 2, University Hospital, LMU Munich, 81377, Munich, Germany
| | - Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto von Guericke University, 39106, Magdeburg, Germany
- Department of Medicine 2, University Hospital, LMU Munich, 81377, Munich, Germany
| | - Sebastian Suerbaum
- Department of Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer Institute, Faculty of Medicine, LMU Munich, 80336, Munich, Germany.
- Institute of Medical Microbiology and Hospital Epidemiology, MHH Hannover Medical School, 30625, Hannover, Germany.
- DZIF German Center for Infection Research, Munich Site, Munich, Germany.
- DZIF German Center for Infection Research, Hannover-Braunschweig Site, Hannover, Germany.
- National Reference Center for Helicobacter pylori, Max von Pettenkofer Institute, 80336, Munich, Germany.
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Helicobacter pylori: Multiple resistance in patients from Bogotá, Colombia. BIOMEDICA 2019; 39:125-134. [PMID: 31529855 DOI: 10.7705/biomedica.v39i3.4437] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Indexed: 12/14/2022]
Abstract
Introduction: The main cause for Helicobacter pylori infection treatment failure is antibiotic resistance, where clarithromycin and metronidazole play the main role. In Colombia, primary resistance as a consequence of the use of these two antibiotics and excessive levofloxacin use is above the accepted limit (13.6%, 83%, and 16%, respectively). Despite this fact, empirical therapies that include the combination of these antibiotics are used in patients with previous therapeutic failure.
Objective: To determine antibiotic resistance in patients previously treated for H. pylori in Bogotá, Colombia.
Materials and methods: We conducted a descriptive study that included ten isolates obtained from five patients with three or four previous failed treatments for H. pylori.
Antibiotic resistance to amoxicillin, clarithromycin, levofloxacin, and metronidazole was investigated by agar dilution and confirmed by DNA sequencing (Magrogen, Korea).
Results: Eight isolates were resistant to two or more antibiotics. All isolates were resistant to levofloxacin. Susceptibility patterns in isolates from the gastric antrum and the body of the stomach were different in three patients.
Conclusion: As far as we know, this is the first evidence of multiple H. pylori resistance in Colombia in previously treated patients. Results demonstrated the consequences of using an ineffective antibiotic scheme and the need to assess antibiotic susceptibility in different anatomical sites of the stomach. The consequences of multiple resistance decrease possible antibiotic effectiveness to eradicate H. pylori in the future.
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Savoldi A, Carrara E, Graham DY, Conti M, Tacconelli E. Prevalence of Antibiotic Resistance in Helicobacter pylori: A Systematic Review and Meta-analysis in World Health Organization Regions. Gastroenterology 2018; 155:1372-1382.e17. [PMID: 29990487 PMCID: PMC6905086 DOI: 10.1053/j.gastro.2018.07.007] [Citation(s) in RCA: 778] [Impact Index Per Article: 111.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2018] [Revised: 06/27/2018] [Accepted: 07/05/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS In 2017, the World Health Organization (WHO) designated clarithromycin-resistant Helicobacter pylori a high priority for antibiotic research and development. However, there are no clear data on the global distribution of resistance or its clinical effects. We performed a systematic review and meta-analysis to assess the distribution of H pylori resistance to commonly used antibiotics and to measure the association between antibiotic resistance and treatment failure. METHODS We searched publication databases for studies that assessed rates of H pylori resistance to clarithromycin, metronidazole, levofloxacin, amoxicillin, or tetracycline. Pooled estimates of primary and secondary resistance and 95% confidence intervals (CIs) were grouped by WHO region. The association between antibiotic resistance and treatment failure was measured by extracting data on treatment efficacy in patients with resistant and susceptible isolates and pooling odds ratios with 95% CIs. RESULTS We identified 178 studies, comprising 66,142 isolates from 65 countries. Primary and secondary resistance rates to clarithromycin, metronidazole, and levofloxacin were ≥15% in all WHO regions, except primary clarithromycin resistance in the Americas (10%; 95% CI, 4%-16%) and South-East Asia region (10%; 95% CI, 5%-16%) and primary levofloxacin resistance in the European region (11%; 95% CI, 9%-13%). There was considerable heterogeneity (I2 > 75%) among all analyses-this might have resulted from the grouping of resistance rates by country. Increasing antibiotic resistance was observed in most WHO regions. Resistance to clarithromycin was significantly associated with failure of clarithromycin-containing regimens (odds ratio, 6.97; 95% CI, 5.23-9.28; P < .001). CONCLUSIONS Resistance of H pylori to antibiotics has reached alarming levels worldwide, which has a great effect on efficacy of treatment. Local surveillance networks are required to select appropriate eradication regimens for each region.
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Affiliation(s)
- Alessia Savoldi
- Division of Infectious Diseases, Department of Internal Medicine I, German Center for Infection Research, University of Tübingen, Tübingen, Germany
| | - Elena Carrara
- Division of Infectious Diseases, Department of Diagnostic and Public Health, G.B. Rossi University Hospital, University of Verona, Verona, Italy
| | - David Y Graham
- Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas
| | - Michela Conti
- Division of Infectious Diseases, Department of Diagnostic and Public Health, G.B. Rossi University Hospital, University of Verona, Verona, Italy
| | - Evelina Tacconelli
- Division of Infectious Diseases, Department of Internal Medicine I, German Center for Infection Research, University of Tübingen, Tübingen, Germany; Division of Infectious Diseases, Department of Diagnostic and Public Health, G.B. Rossi University Hospital, University of Verona, Verona, Italy.
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Diab M, El-Shenawy A, El-Ghannam M, Salem D, Abdelnasser M, Shaheen M, Abdel-Hady M, El-Sherbini E, Saber M. Detection of antimicrobial resistance genes of Helicobacter pylori strains to clarithromycin, metronidazole, amoxicillin and tetracycline among Egyptian patients. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2018. [DOI: 10.1016/j.ejmhg.2018.01.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Droplet Digital PCR-Based Detection of Clarithromycin Resistance in Helicobacter pylori Isolates Reveals Frequent Heteroresistance. J Clin Microbiol 2018; 56:JCM.00019-18. [PMID: 29925646 DOI: 10.1128/jcm.00019-18] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Accepted: 06/15/2018] [Indexed: 12/14/2022] Open
Abstract
Chronic infection with Helicobacter pylori causes peptic ulcers and stomach cancer in a subset of infected individuals. While standard eradication therapy includes multiple antibiotics, treatment failure due to resistance is an increasing clinical problem. Accurate assessment of H. pylori antimicrobial resistance has been limited by slow growth and sampling of few isolates per subject. We established a method to simultaneously quantify H. pylori clarithromycin-resistant (mutant) and -susceptible (wild-type) 23S rRNA gene alleles in both stomach and stool samples using droplet digital PCR (ddPCR). In 49 subjects, we assessed the performance of these assays alongside clarithromycin MIC testing of up to 16 H. pylori isolates per subject and included both cancer (25 subjects) and noncancer (24 subjects) cases. Gastric ddPCR and H. pylori culture showed agreement with urea breath test (UBT) detection of infection in 94% and 88% of subjects, respectively, while stool ddPCR showed agreement with UBT in 92% of subjects. Based on MIC testing of 43 culture-positive cases, 20 subjects had only susceptible isolates, 14 had a mix of susceptible and resistant isolates, and 9 had only resistant isolates. ddPCR of gastric samples indicated that 21 subjects had only wild-type alleles, 13 had a mixed genotype, and 9 had only mutant alleles. Stool ddPCR detected mutant alleles in four subjects for which mutant alleles were not detected by stomach ddPCR, and no resistant isolates were cultured. Our results indicate that ddPCR detects H. pylori clarithromycin resistance-associated genotypes, especially in the context of heteroresistance.
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Characterization of clarithromycin heteroresistance among Helicobacter pylori strains isolated from the antrum and corpus of the stomach. Folia Microbiol (Praha) 2018; 64:143-151. [PMID: 30097895 DOI: 10.1007/s12223-018-0637-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Accepted: 08/06/2018] [Indexed: 02/07/2023]
Abstract
Mixed infections and heteroresistance of Helicobacter pylori contribute to decreased efficacy of treatments. This study aimed to investigate frequency of clarithromycin heteroresistance and its link with mixed infections, medication history, and disease severity. A total of 40 pairs of H. pylori strains were isolated from the antrum and corpus of 97 patients. Susceptibility of the strains to clarithromycin was measured by agar dilution method. Site-specific mutations of 23S rRNA at A2143G, A2142G, and A2142C positions were analyzed by PCR and genomic relatedness of pairs of the strains was determined by random amplified polymorphic DNA (RAPD)-PCR. The results showed a prevalence of 35% (14/40) clarithromycin resistance. Diversity of the antrum and corpus isolates in resistance to clarithromycin was detected among 17.5% (7/40) of the patients. Similarly, diversity in MIC value was also detected in two patients infected with the sensitive strains. Significant difference in frequency of resistance was detected among patients with peptic ulcer disease (PUD) (MIC90 32 μg/mL) and severe gastritis (MIC90 16 μg/mL), compared with those who suffered from non-ulcer dyspepsia (NUD) (MIC90 8 μg/mL) and chronic gastritis (MIC90 0.25 μg/mL). MIC values showed 8-32 folds increased levels in the corpus. A2142G, A2143G, and A2142C mutations were detected in three, two, and two patients, respectively, but not observed in 46% of the resistant strains. RAPD-PCR fingerprints showed identical molecular patterns for the isolates of the corpus and antrum in each patient. In conclusion, microevolution of H. pylori strains during chronic infection, rather than mixed infection, and inappropriate medication appear to be main reasons of treatment failure in adults.
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Abstract
In addition to its role in gastric conditions,
Helicobacter pylori has been found to contribute to the development of several non-gastric issues in recent years. Eradication therapy is the only effective management strategy to minimize the
H. pylori-related gastric cancer and extra-gastric complications. For an effective “test and treat” strategy, diagnosis and therapy are both important. Because the infection is usually asymptomatic, patient selection is a critical issue for timely diagnosis and many clinical and demographic factors should be considered. Clarithromycin and metronidazole resistance rates also need to be considered while eradication therapy is offered. In this report, we discuss the issues which must be taken into account for the correct and timely diagnosis and for the antibiotic therapy-based management of
H. pylori infection.
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Affiliation(s)
- Shamshul Ansari
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu-City, Oita, 879-5593, Japan
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu-City, Oita, 879-5593, Japan.,Department of Medicine-Gastroenterology, Baylor College of Medicine, 2002 Holcombe Boulevard, Houston, TX, 77030, USA
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Szadkowski A, Zemlak M, Muszyński J. Effectiveness of Helicobacter pylori eradication established on the basis of examination of antibiotic resistance of the bacteria. PRZEGLAD GASTROENTEROLOGICZNY 2018; 13:93-98. [PMID: 30002766 PMCID: PMC6040107 DOI: 10.5114/pg.2018.75821] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Accepted: 06/30/2017] [Indexed: 12/17/2022]
Abstract
INTRODUCTION The treatment of Helicobacter pylori (HP) tends to be empirical despite a high number of failures (over 20%). The efficacy of eradication therapies is declining, reaching in some countries 60%, which correlates inversely with the growing drug resistance of the bacteria. AIM Given the frequent inefficacy of the hitherto proposed treatment schemes for HP infection, an attempt was made to assess the efficacy of a therapy based on the antibiotic resistance of the cultured bacteria, and to analyse factors with possible contribution to the inefficacy of HP eradication treatment. MATERIAL AND METHODS The study covered patients from one region of Central Poland in the years 2005-2015. The total material for bacteriological assessment was collected from 154 patients who had previously been subject to HP eradication treatment at least two times, including 80 women and 74 men, reporting subsequently to the Clinic. RESULTS The efficacy of the antibiogram-based treatment was merely 65.62%. A low, but slightly higher than expected, resistance to amoxicillin (3.48%) and tetracycline (2.27%), as well as to clarithromycin (27.27%) and metronidazole (70.69%), was established. CONCLUSIONS In Polish patients resistance to clarithromycin and metronidazole of HP is high and becoming increasingly resistant; however, we found low bacterial resistance to tetracycline.
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Affiliation(s)
| | - Magdalena Zemlak
- Department of Gastroenterology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Jacek Muszyński
- Department of Gastroenterology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
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Gong Y, Yuan Y. Resistance mechanisms of Helicobacter pylori and its dual target precise therapy. Crit Rev Microbiol 2018; 44:371-392. [PMID: 29293032 DOI: 10.1080/1040841x.2017.1418285] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Helicobacter pylori drug resistance presents a significant challenge to the successful eradication of this pathogen. To find strategies to improve the eradication efficacy of H. pylori, it is necessary to clarify the resistance mechanisms involved. The mechanisms of H. pylori drug resistance can be investigated from two angles: the pathogen and the host. A comprehensive understanding of the molecular mechanisms of H. pylori resistance based on both pathogen and host would aid the implementation of precise therapy, or ideally "dual target precise therapy" (bacteria and host-specific target therapy). In recent years, with increased understanding of the mechanisms of H. pylori resistance, the focus of eradication has shifted from disease-specific to patient-specific treatment. The implementation of "precision medicine" has also provided a new perspective on the treatment of infectious diseases. In this article, we systematically review current research on H. pylori drug resistance from the perspective of both the pathogen and the host. We also review therapeutic strategies targeted to pathogen and host factors that are aimed at achieving precise treatment of H. pylori.
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Affiliation(s)
- Yuehua Gong
- a Tumor Etiology and Screening Department of Cancer Institute and General Surgery , the First Hospital of China Medical University , Shenyang , China.,b Key Laboratory of Cancer Etiology and Prevention (China Medical University) Liaoning Provincial Education Department , Shenyang , China.,c National Clinical Research Center for Digestive Diseases , Xi'an , China
| | - Yuan Yuan
- a Tumor Etiology and Screening Department of Cancer Institute and General Surgery , the First Hospital of China Medical University , Shenyang , China.,b Key Laboratory of Cancer Etiology and Prevention (China Medical University) Liaoning Provincial Education Department , Shenyang , China.,c National Clinical Research Center for Digestive Diseases , Xi'an , China
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Oikawa R, Watanabe Y, Miyamoto S, Sato Y, Ono S, Mabe K, Yamamoto H, Kato M, Itoh F. Enrichment of Helicobacter pylori mutant strains after eradication therapy analyzed by gastric wash-based quantitative pyrosequencing. Tumour Biol 2017; 39:1010428317734865. [PMID: 28990461 DOI: 10.1177/1010428317734865] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The eradication of Helicobacter pylori reduces the risk of gastric cancer. A clear understanding of the factors underlying mixed infection with multiple clarithromycin-susceptible and clarithromycin-resistant H. pylori strains is necessary to design more effective therapies against H. pylori. We aimed to assess how the abundance and prevalence of H. pylori strains vary after clarithromycin-based eradication therapy. Using gastric wash samples, which represent the entire stomach, we sequentially analyzed the abundance and prevalence of H. pylori DNA by 23S ribosomal RNA pyrosequencing before and 1, 2, and 3 years after eradication therapy. Low levels of H. pylori DNA were still detectable at the first-year follow-up in all samples with negative post-treatment urea breath test results. The abundance of H. pylori DNA decreased significantly until the 2-year follow-up, but it switched to an increase at the 3-year follow-up. Importantly, the ratio of the prevalence of mutant strains to the prevalence of wild-type strains had already increased at the first-year follow-up and continued to increase, suggesting the selection and growth of clarithromycin-resistant strains during the follow-up periods. Being sensitive and representative, our assay will be useful in effectively addressing gastric cancer development by enhancing the long-term success of intervention strategies and consecutive surveillance for H. pylori eradication.
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Affiliation(s)
- Ritsuko Oikawa
- 1 Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Yoshiyuki Watanabe
- 1 Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.,2 Department of Internal Medicine, Kawasaki Rinko General Hospital, Kawasaki, Japan
| | - Shuichi Miyamoto
- 3 Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Yoshinori Sato
- 1 Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Shoko Ono
- 4 Division of Endoscopy, Hokkaido University Hospital, Sapporo, Japan
| | - Katsuhiro Mabe
- 5 Department of Gastroenterology, National Hospital Organization Hakodate Hospital, Hakodate, Japan
| | - Hiroyuki Yamamoto
- 1 Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Mototsugu Kato
- 5 Department of Gastroenterology, National Hospital Organization Hakodate Hospital, Hakodate, Japan
| | - Fumio Itoh
- 1 Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan
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Mascellino MT, Porowska B, De Angelis M, Oliva A. Antibiotic susceptibility, heteroresistance, and updated treatment strategies in Helicobacter pylori infection. Drug Des Devel Ther 2017; 11:2209-2220. [PMID: 28814829 PMCID: PMC5546184 DOI: 10.2147/dddt.s136240] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
In this review, we discuss the problem of antibiotic resistance, heteroresistance, the utility of cultures and antibiotic susceptibility tests in Helicobacter pylori (Hp) eradication, as well as the updated treatment strategies for this infection. The prevalence of antibiotic resistance is increasing all over the world, especially for metronidazole and clarithromycin, because of their heavy use in some geographical areas. Heteroresistance (simultaneous presence of both susceptible and resistant strains in different sites of a single stomach) is another important issue, as an isolate could be mistakenly considered susceptible if a single biopsy is used for antimicrobial tests. We also examined literature data regarding eradication success rates of culture-guided and empiric therapies. The empiric therapy and the one based on susceptibility testing, in Hp eradication, may depend on several factors such as concomitant diseases, the number of previous antibiotic treatments, differences in bacterial virulence in individuals with positive or negative cultures, together with local antibiotic resistance patterns in real-world settings. Updated treatment strategies in Hp infection presented in the guidelines of the Toronto Consensus Group (2016) are reported. These suggest to prolong eradication therapy up to 14 days, replacing the old triple therapy with a quadruple therapy based on proton pump inhibitor (PPI), bismuth, metronidazole, and tetracycline for most of the patients, or as an alternative quadruple therapy without bismuth, based on the use of PPI, amoxicillin, metronidazole, and clarithromycin. The new drug vonoprazan, a first-in-class potassium-competitive acid blocker recently approved in Japan, is also considered to be a promising solution for Hp eradication, even for clarithromycin-resistant strains. Furthermore, there is growing interest in finding new therapeutic strategies, such as the development of vaccines or the use of natural resources, including probiotics, plants, or nutraceuticals.
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Affiliation(s)
| | - Barbara Porowska
- Department of Cardio-Thoracic, Vascular, General Surgery and of Organ Transplants, Policlinico Umberto I, Rome, Italy
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Bilgilier C, Stadlmann A, Makristathis A, Thannesberger J, Kastner MT, Knoflach P, Steiner P, Schöniger-Hekele M, Högenauer C, Blesl A, Datz C, Huber-Schönauer U, Schöfl R, Wewalka F, Püspök A, Mitrovits N, Leiner J, Tilg H, Effenberger M, Moser M, Siebert F, Hinterberger I, Wurzer H, Stupnicki T, Watzinger N, Gombotz G, Hubmann R, Klimpel S, Biowski-Frotz S, Schrutka-Kölbl C, Graziadei I, Ludwiczek O, Kundi M, Hirschl AM, Steininger C. Prospective multicentre clinical study on inter- and intrapatient genetic variability for antimicrobial resistance of Helicobacter pylori. Clin Microbiol Infect 2017; 24:267-272. [PMID: 28669844 DOI: 10.1016/j.cmi.2017.06.025] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 06/21/2017] [Accepted: 06/22/2017] [Indexed: 02/06/2023]
Abstract
OBJECTIVES We report on a large prospective, multicentre clinical investigation on inter- and intrapatient genetic variability for antimicrobial resistance of Helicobacter pylori. METHODS Therapy-naive patients (n = 2004) who had undergone routine diagnostic gastroscopy were prospectively included from all geographic regions of Austria. Gastric biopsy samples were collected separately from antrum and corpus. Samples were analysed by histopathology and real-time PCR for genotypic resistance to clarithromycin and quinolones. Clinical and demographic information was analysed in relation to resistance patterns. RESULTS H. pylori infection was detected in 514 (26%) of 2004 patients by histopathology and confirmed in 465 (90%) of 514 patients by real-time PCR. PCR results were discordant for antrum and corpus in 27 (5%) of 514 patients, indicating inhomogeneous infections. Clarithromycin resistance rates were 17% (77/448) and 19% (84/455), and quinolone resistance rates were 12% (37/310) and 10% (32/334) in antrum and corpus samples, respectively. Combination of test results per patient yielded resistance rates of 21% (98/465) and 13% (50/383) for clarithromycin and quinolones, respectively. Overall, infection with both sensitive and resistant H. pylori was detected in 65 (14%) of 465 patients. CONCLUSIONS Anatomically inhomogeneous infection with different, multiple H. pylori strains is common. Prospective clinical study design, collection of samples from multiple sites and microbiologic methods that allow the detection of coinfections are mandatory for collection of reliable data on antimicrobial resistance patterns in representative patient populations. (ClinicalTrials.gov identifier: NCT02925091).
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Affiliation(s)
- C Bilgilier
- Department of Internal Medicine I, Division of Infectious Diseases and Tropical Medicine, Austria
| | - A Stadlmann
- Department of Internal Medicine I, Division of Infectious Diseases and Tropical Medicine, Austria
| | - A Makristathis
- Department of Laboratory Medicine, Division of Clinical Microbiology, Austria
| | - J Thannesberger
- Department of Internal Medicine I, Division of Infectious Diseases and Tropical Medicine, Austria
| | - M-T Kastner
- Department of Internal Medicine I, Division of Infectious Diseases and Tropical Medicine, Austria
| | - P Knoflach
- Department of Internal Medicine I, Klinikum Wels-Grieskirchen, Wels, Austria
| | - P Steiner
- Department of Internal Medicine I, Klinikum Wels-Grieskirchen, Wels, Austria
| | - M Schöniger-Hekele
- Department of Medicine III, Division of Gastroenterology and Hepatology, Austria
| | - C Högenauer
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Austria
| | - A Blesl
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Austria
| | - C Datz
- Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private Medical University Salzburg, Oberndorf bei Salzburg, Austria
| | - U Huber-Schönauer
- Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private Medical University Salzburg, Oberndorf bei Salzburg, Austria
| | - R Schöfl
- Department of Internal Medicine IV, Division of Gastroenterology and Hepatology, Ordensklinikum Linz, Elisabethinen, Austria
| | - F Wewalka
- Department of Internal Medicine IV, Division of Gastroenterology and Hepatology, Ordensklinikum Linz, Elisabethinen, Austria
| | - A Püspök
- Department of Internal Medicine II, Hospital of the Brothers of Saint John of God Eisenstadt, Eisenstadt, Austria
| | - N Mitrovits
- Department of Internal Medicine II, Hospital of the Brothers of Saint John of God Eisenstadt, Eisenstadt, Austria
| | - J Leiner
- Department of Internal Medicine, Ladislaus Batthyány-Strattmann Hospital Kittsee, Kittsee, Austria
| | - H Tilg
- Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Austria
| | - M Effenberger
- Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Austria
| | - M Moser
- Ordination Dr Moser, Hall/Tyrol, Austria
| | - F Siebert
- Department of Internal Medicine, Hospital of the Brothers of Saint John of God St Veit/Glan, St Veit, Austria
| | - I Hinterberger
- Department of Internal Medicine, Hospital of the Brothers of Saint John of God St Veit/Glan, St Veit, Austria
| | - H Wurzer
- Department of Internal Medicine, LKH Graz South-West, Graz, Austria
| | - T Stupnicki
- Department of Internal Medicine, LKH Graz South-West, Graz, Austria
| | - N Watzinger
- Department of Internal Medicine, Hospital Group Feldbach-Fürstenfeld, Feldbach, Austria
| | - G Gombotz
- Department of Internal Medicine, Hospital Group Feldbach-Fürstenfeld, Feldbach, Austria
| | - R Hubmann
- Ordination Dr Rainer Hubmann, Linz, Austria
| | - S Klimpel
- Ordination Dr Siegfried Klimpel, Traun, Austria
| | | | | | - I Graziadei
- Department of Internal Medicine, Academic Teaching Hospital, Hall/Tyrol, Austria
| | - O Ludwiczek
- Department of Internal Medicine, Academic Teaching Hospital, Hall/Tyrol, Austria
| | - M Kundi
- Department of Environmental Health, Center for Public Health, Medical University of Vienna, Austria
| | - A M Hirschl
- Department of Laboratory Medicine, Division of Clinical Microbiology, Austria
| | - C Steininger
- Department of Internal Medicine I, Division of Infectious Diseases and Tropical Medicine, Austria.
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