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Umar Z, Tang JW, Marshall BJ, Tay ACY, Wang L. Rapid diagnosis and precision treatment of Helicobacter pylori infection in clinical settings. Crit Rev Microbiol 2025; 51:369-398. [PMID: 38910506 DOI: 10.1080/1040841x.2024.2364194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 05/08/2024] [Accepted: 05/25/2024] [Indexed: 06/25/2024]
Abstract
Helicobacter pylori is a gram-negative bacterium that colonizes the stomach of approximately half of the worldwide population, with higher prevalence in densely populated areas like Asia, the Caribbean, Latin America, and Africa. H. pylori infections range from asymptomatic cases to potentially fatal diseases, including peptic ulcers, chronic gastritis, and stomach adenocarcinoma. The management of these conditions has become more difficult due to the rising prevalence of drug-resistant H. pylori infections, which ultimately lead to gastric cancer and mucosa-associated lymphoid tissue (MALT) lymphoma. In 1994, the International Agency for Research on Cancer (IARC) categorized H. pylori as a Group I carcinogen, contributing to approximately 780,000 cancer cases annually. Antibiotic resistance against drugs used to treat H. pylori infections ranges between 15% and 50% worldwide, with Asian countries having exceptionally high rates. This review systematically examines the impacts of H. pylori infection, the increasing prevalence of antibiotic resistance, and the urgent need for accurate diagnosis and precision treatment. The present status of precision treatment strategies and prospective approaches for eradicating infections caused by antibiotic-resistant H. pylori will also be evaluated.
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Affiliation(s)
- Zeeshan Umar
- Marshall Laboratory of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen, Guangdong Province, China
- Laboratory Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong Province, China
| | - Jia-Wei Tang
- Laboratory Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong Province, China
- The Marshall Centre for Infectious Diseases Research and Training, The University of Western Australia, Crawley, Western Australia, China
| | - Barry J Marshall
- Marshall Laboratory of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen, Guangdong Province, China
- The Marshall Centre for Infectious Diseases Research and Training, The University of Western Australia, Crawley, Western Australia, China
- Marshall International Digestive Diseases Hospital, Zhengzhou University, Zhengzhou, Henan Province, China
- Marshall Medical Research Center, Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Alfred Chin Yen Tay
- Marshall Laboratory of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen, Guangdong Province, China
- The Marshall Centre for Infectious Diseases Research and Training, The University of Western Australia, Crawley, Western Australia, China
- Marshall International Digestive Diseases Hospital, Zhengzhou University, Zhengzhou, Henan Province, China
- Marshall Medical Research Center, Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Liang Wang
- Laboratory Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong Province, China
- Division of Microbiology and Immunology, School of Biomedical Sciences, The University of Western Australia, Crawley, Western Australia, China
- Center for Precision Health, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, China
- School of Agriculture and Food Sustainability, University of Queensland, Brisbane, Queensland, Australia
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Gareayaghi N, Kocazeybek B. Detection of A2143G, A2142C, and A2142G Point Mutations with Real-Time PCR in Stool Specimens from Children Infected with Helicobacter pylori. Diagnostics (Basel) 2022; 12:2119. [PMID: 36140521 PMCID: PMC9497693 DOI: 10.3390/diagnostics12092119] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/26/2022] [Accepted: 08/29/2022] [Indexed: 11/16/2022] Open
Abstract
Reports have indicated an increasing prevalence of clarithromycin resistance in children relative to adults. Thus, it is important to investigate primary clarithromycin resistance before therapy to avoid treatment failure. A2142G, A2143G, and A2142C point mutations in the peptidyltransferase region of the 23S ribosomal RNA (rRNA) of Helicobacter pylori (H. pylori) strains isolated from children with gastrointestinal symptoms and asymptomatic children were evaluated via real-time polymerase chain reaction (RT-PCR) using fecal DNA samples. The presence of H. pylori was determined using a fecal H. pylori antigen enzyme-linked immunosorbent assay (ELISA) kit from the stools of children (n = 543). A2143G, A2142C, and A2142G point mutations were detected via RT-PCR and confirmed by sequencing the 23S rDNA. Fecal H. pylori antigen testing was positive in 101 symptomatic (49) and asymptomatic (52) children. A significant difference was found between the 0-5- and 5-18-year-old groups in terms of the A2143G and A2142G point mutations (p = 0.001). The A2142C mutation was not detected. There was a significant difference in the A2143G mutation between the symptomatic and asymptomatic 5-18-year-old children (p = 0.019). Macrolides are frequently used to treat upper respiratory tract infections in children due to their selective pressure effect. We suggest that H. pylori strains carrying mutations in the 23S RNA subunit conferring clarithromycin resistance may lead to an intense inflammatory response in the gastric epithelial cells, allowing them to proliferate more rapidly and causing possible diarrhea, halitosis, or abdominal pain in children.
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Affiliation(s)
- Nesrin Gareayaghi
- Istanbul Sisli Hamidiye Etfal Training and Research Hospital, Center for Blood, University of Health Sciences, Istanbul 34098, Turkey
| | - Bekir Kocazeybek
- Department of Medical Microbiology, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Istanbul 34098, Turkey
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Dai J, Zhao J, Mao L, Hu Y, Lv B. Study on the value of antibiotic-resistant gene detection in Helicobacter pylori in China. Exp Ther Med 2022; 23:228. [PMID: 35222705 PMCID: PMC8815056 DOI: 10.3892/etm.2022.11153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 11/03/2021] [Indexed: 11/05/2022] Open
Abstract
The aim of the present study was to explore the value of detecting antibiotic-resistant genes in Helicobacter pylori (H. pylori) and the association between genotype and antibiotic resistance. Two gastric mucosa samples from each H. pylori-positive patient were collected. Each patient's H. pylori sample was cultured in vitro, and the agar plate dilution method was conducted. In addition, all patient samples were analyzed for the detection of antibiotic resistance-related mutant genes and VacA gene genotypes. The association between VacA genotypes and antibiotic resistance was also determined and the value of mutant gene detection in predicting H. pylori resistance to antibiotics was evaluated. In total, 133 H. pylori-positive patients were enrolled. A total of 22 strains of H. pylori failed to grow in in vitro culture and 25 strains were negative in a H. pylori gene test. Among 108 strains detected by PCR, a total of 39 VacA s1m1 strains, 69 VacA s1m2 strains and no VacA s2 strain were identified. There was no significant association between VacA genotypes and antibiotic resistance. The mutation rates of G616A in the rdxA gene, T87A, G91A, A91G and G91T in the gyrA gene and A2143G and A2142G in the 23S rRNA gene were 32.1, 32.3, 22.6, 12.9, 6.5, 81.8 and 0.0%, respectively. Among these mutant sites, the mutation coincidence rates were as follows, according to the agar plate dilution method: rdxA G616A (81.8%), gyrA G91T (66.7%), gyrA G91A (54.5%), 23 S rRNA A2143G (49.1%), gyrA T87A (45.5%), gyrA A91G (33.3%), penicillin-binding protein 1 (PBP1) C556G (0.0%), PBP1 A562T (0.0%), PBP1 A562G (0.0%) and 16 S rRNA 926-927 (AT-GT) (0.0%). VacA m subtypes were not associated with H. pylori antibiotic resistance. In conclusion, the present findings suggested that the detection of related mutant genes had a clinical application value in predicting the antibiotic resistance of H. pylori, particularly resistance to clarithromycin and levofloxacin.
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Affiliation(s)
- Jinfeng Dai
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310006, P.R. China
| | - Jing Zhao
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310006, P.R. China
| | - Liqi Mao
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310006, P.R. China
| | - Yue Hu
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310006, P.R. China
| | - Bin Lv
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310006, P.R. China
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Park CG, Kim S, Lee EJ, Jeon HS, Han S. Clinical relevance of point mutations in the 23S rRNA gene in Helicobacter pylori eradication: A prospective, observational study. Medicine (Baltimore) 2018; 97:e11835. [PMID: 30113472 PMCID: PMC6112885 DOI: 10.1097/md.0000000000011835] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Clarithromycin-based triple therapy is prescribed worldwide for Helicobacter pylori eradication. However, increases in the clarithromycin resistance of H pylori are thought to be responsible for eradication failure. Here, we studied whether point mutations in domain V of the 23S rRNA gene can affect H pylori eradication failure in a prospective, open-label, observational study. Of the 755 enrolled patients, 299 patients (39.6%) had positive Campylobacter-like organism (CLO) tests. DNA sequencing analysis of H pylori 23S rRNA in 295 patients revealed that 2143G was the most frequent point mutation (24.7% of patients), followed by the 2182T mutation (11.5%). The overall eradication failure rate was 20.9% (42/201) in clarithromycin-based triple therapy. Patients with the 2143G had an approximately 60% eradication failure rate, which suggested that 2143G was a high-risk genotype for eradication failure. Patients with the 2182C genotype without 2143G had an 8.7% failure rate, and patients without 2143G or 2182C had only a 4.3% failure rate. The presence of 2143G, which was associated with previous eradication history and female sex, was an independent risk factor for eradication failure. In conclusion, the 2143G point mutation in the 23S rRNA of H pylori was an independent risk factor for eradication failure in clarithromycin-based triple therapy. Personalized tailored therapy based on the genotypes of 23S rRNA can increase eradication success rates in H pylori infections.
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Affiliation(s)
| | | | - Eun-Ju Lee
- Laboratory for Arthritis and Bone Biology, Fatima Research Institute, Daegu Fatima Hospital
| | | | - Seungwoo Han
- Laboratory for Arthritis and Bone Biology, Fatima Research Institute, Daegu Fatima Hospital
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea
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A Novel Stool PCR Test for Helicobacter pylori May Predict Clarithromycin Resistance and Eradication of Infection at a High Rate. J Clin Microbiol 2017; 55:2400-2405. [PMID: 28515219 DOI: 10.1128/jcm.00506-17] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Accepted: 05/13/2017] [Indexed: 02/06/2023] Open
Abstract
Clarithromycin-based regimens are commonly used as a first-line therapy for Helicobacter pylori-positive patients; however, resistance to clarithromycin has led to treatment failures. The aim of this study was to evaluate the feasibility of using stool samples to detect the presence of H. pylori DNA while concurrently detecting mutations associated with resistance to clarithromycin. For this purpose, total DNA was extracted from 294 raw stool specimens from H. pylori-positive and -negative patients. TaqMan real-time PCR amplification was used to detect the presence of H. pylori as well as to predict the phenotype of the organism and the related outcome for patients treated with clarithromycin. Clarithromycin resistance was determined upon analysis of the PCR result. Patients were also tested by a urea breath test and were subjected to esophagogastroduodenoscopy, followed by histology, culture, and a rapid urease test, in order to obtain a consensus patient infection status. Of 294 total stool samples, 227 were deemed true positive. The sensitivity of H. pylori detection by PCR was 93.8%. Of 213 true-positive samples that were sequenced, 36.2% showed point mutations associated with clarithromycin resistance (A2142C, A2142G, A2143G). The final correlation of the mutant genotypes as determined by sequencing with the eradication of infection was 86%. We found that Helicobacter pylori DNA can be detected in human stool specimens with high sensitivity and can therefore be used to determine the presence of the bacterium without obtaining a biopsy sample. Moreover, genotypic resistance to clarithromycin can be predicted without obtaining a biopsy sample, facilitating the choice of the right therapeutic approach.
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Arslan N, Yılmaz Ö, Demiray-Gürbüz E. Importance of antimicrobial susceptibility testing for the management of eradication in Helicobacter pylori infection. World J Gastroenterol 2017; 23:2854-2869. [PMID: 28522904 PMCID: PMC5413781 DOI: 10.3748/wjg.v23.i16.2854] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 02/06/2017] [Accepted: 03/30/2017] [Indexed: 02/06/2023] Open
Abstract
The management of Helicobacter pylori (H. pylori) infection treatment differs from the common treatment protocol for other infectious diseases. Because culture- or molecular-guided approaches face several practical issues, such as the invasive procedures required to obtain gastric biopsy specimens and the lack of availability of routine laboratory testing in some places, H. pylori treatment includes the administration of two or three empirically selected antibiotics combined with a proton pump inhibitor rather than evidence-based eradication treatment. The efficacy of empirical therapy is decreasing, mostly due to increasing multiple resistance. Multiresistance to levofloxacin, clarithromycin, and metronidazole, which are commonly used in empirical treatments, appears to have increased in many countries. Mutations play a primary role in the antimicrobial resistance of H. pylori, but many different mechanisms can be involved in the development of antibiotic resistance. Determining and understanding these possible mechanisms might allow the development of new methods for the detection of H. pylori and the determination of antimicrobial resistance. A treatment based on the detection of antimicrobial resistance is usually more effective than empirical treatment. Nevertheless, such an approach before treatment is still not recommended in the Maastricht guidelines due to the difficulty associated with the routine application of available culture- or molecular-based susceptibility tests, which are usually administered in cases of treatment failure. The management of first and rescue treatments requires further research due to the steadily increase in antimicrobial resistance.
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Demiray-Gürbüz E, Yılmaz Ö, Olivares AZ, Gönen C, Sarıoğlu S, Soytürk M, Tümer S, Altungöz O, Şimşek İ, Perez Perez GI. Rapid identification of Helicobacter pylori and assessment of clarithromycin susceptibility from clinical specimens using FISH. JOURNAL OF PATHOLOGY CLINICAL RESEARCH 2016; 3:29-37. [PMID: 28138399 PMCID: PMC5259560 DOI: 10.1002/cjp2.57] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Revised: 08/03/2016] [Accepted: 08/12/2016] [Indexed: 12/21/2022]
Abstract
Helicobacter pylori remains one of the most common bacterial infections worldwide. Clarithromycin resistance is the most important cause of H. pylori eradication failures. Effective antibiotic therapies in H. pylori infection must be rapidly adapted to local resistance patterns. We investigated the prevalence of clarithromycin resistance due to mutations in positions 2142 and 2143 of 23SrRNA gene of H. pylori by fluorescence in situ hybridisation (FISH), and compared with culture and antimicrobial susceptibility testing in 234 adult patients with dyspepsia who were enrolled. Antrum and corpus biopsy specimens were obtained for rapid urease test, histopathology and culture. Epsilometer test was used to assess clarithromycin susceptibility. H. pylori presence and clarithromycin susceptibility were determined by FISH in paraffin‐embedded biopsy specimens. We found that 164 (70.1%) patients were positive for H. pylori based on clinical criteria, 114 (69.5% CI 62.5–76.6%) were culture positive, and 137 (83.5% CI 77.8–89.2%) were FISH positive. Thus the sensitivity of FISH was significantly superior to that of culture. However specificity was not significantly different (91.4 versus 100.0%, respectively). The resistance rate to clarithromycin for both antrum and corpus was detected in H. pylori‐positive patients; 20.2% by FISH and 28.0% by E‐test.The concordance between E‐test and FISH was only 89.5% due to the presence of point mutations different from A2143G, A2142G or A2142C. We conclude that FISH is significantly more sensitive than culture and the E‐test for the detection of H. pylori and for rapid determinination of claritromycin susceptibility. The superior hybridisation efficiency of FISH is becoming an emerging molecular tool as a reliable, rapid and sensitive method for the detection and visualisation of H. pylori, especially when the management of H. pylori eradication therapy is necessary. This is particularly important for the treatment of patients with H. pylori eradication failure.
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Affiliation(s)
- Ebru Demiray-Gürbüz
- Department of Medical Microbiology, Faculty of Medicine Dokuz Eylül University İzmir Turkey
| | - Özlem Yılmaz
- Department of Medical Microbiology, Faculty of Medicine Dokuz Eylül University İzmir Turkey
| | - Asalia Z Olivares
- Departments of Medicine and Microbiology New York University, School of Medicine, NYUSM New York NY USA
| | - Can Gönen
- Departments of Gastroenterology, Faculty of Medicine Dokuz Eylül University Izmir Turkey
| | - Sülen Sarıoğlu
- Pathology, Faculty of Medicine Dokuz Eylül University Izmir Turkey
| | - Müjde Soytürk
- Departments of Gastroenterology, Faculty of Medicine Dokuz Eylül University Izmir Turkey
| | - Sait Tümer
- Medical Biology and Genetics, Faculty of Medicine Dokuz Eylül University İzmir Türkiye
| | - Oğuz Altungöz
- Medical Biology and Genetics, Faculty of Medicine Dokuz Eylül University İzmir Türkiye
| | - İlkay Şimşek
- Departments of Gastroenterology, Faculty of Medicine Dokuz Eylül University Izmir Turkey
| | - Guillermo I Perez Perez
- Departments of Medicine and Microbiology New York University, School of Medicine, NYUSM New York NY USA
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Recent Insights into Antibiotic Resistance in Helicobacter pylori Eradication. Gastroenterol Res Pract 2012; 2012:723183. [PMID: 22829809 PMCID: PMC3398622 DOI: 10.1155/2012/723183] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2012] [Revised: 06/18/2012] [Accepted: 06/18/2012] [Indexed: 12/13/2022] Open
Abstract
Antibiotics have been useful in the treatment of H. pylori-related benign and malignant gastroduodenal diseases. However, emergence of antibiotic resistance often decreases the eradication rates of H. pylori infections. Many factors have been implicated as causes of treatment failure, but the main antibiotic resistance mechanisms described to date are due to point mutations on the bacterial chromosome, a consequence of a significantly phenotypic variation in H. pylori. The prevalence of antibiotic (e.g., clarithromycin, metronidazole, tetracycline, amoxicillin, and furazolidone) resistance varies among different countries; it appears to be partly determined by geographical factors. Since the worldwide increase in the rate of antibiotic resistance represents a problem of relevance, some studies have been performed in order to identify highly active and well-tolerated anti-H. pylori therapies including sequential, concomitant quadruple, hybrid, and quadruple therapy. These represent a promising alternatives in the effort to overcome the problem of resistance. The aim of this paper is to review the current status of antibiotic resistance in H. pylori eradication, highlighting the evolutionary processes in detail at alternative approaches to treatment in the past decade. The underlying resistance mechanisms will be also followed.
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Evaluation of a new test, genotype HelicoDR, for molecular detection of antibiotic resistance in Helicobacter pylori. J Clin Microbiol 2009; 47:3600-7. [PMID: 19759218 DOI: 10.1128/jcm.00744-09] [Citation(s) in RCA: 124] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The eradication rate of Helicobacter pylori by standard therapy is decreasing due to antibiotic resistance, mainly to clarithromycin. Our aim was to provide a new molecular test to guide the treatment of new and relapsed cases. We first studied 126 H. pylori strains for phenotypic (MIC) and genotypic resistance to clarithromycin (rrl mutation) and levofloxacin (gyrA mutation) and then developed a DNA strip genotyping test on the basis of the correlation results and literature data. Clinical strains (n = 92) and gastric biopsy specimens containing H. pylori (n = 105) were tested blindly with the new molecular test GenoType HelicoDR. The presence of mutations or the absence of hybridization with wild-type sequences was predictive, in rrl for clarithromycin resistance in 91 cases (mostly the A2147G mutation) and in gyrA for levofloxacin resistance in 58 cases (mutations at codon 87 or 91). Genotyping revealed a mix of genotypes in 33% of the cases, reflecting a coinfection or selection for resistant mutants. The sensitivity and specificity of detecting resistance were 94% and 99% for clarithromycin and 87% and 98.5% for levofloxacin, respectively. The concordance scores were 0.96 for clarithromycin and 0.94 for levofloxacin. With global resistance rates of 46% for clarithromycin and 25% for levofloxacin, which were observed for consecutive positive biopsy specimens from 2007 and 2008, the positive and negative predictive values for detecting resistance were 99% and 94% for clarithromycin and 96% and 96% for fluoroquinolone. GenoType HelicoDR is efficient at detecting mutations predictive of antibiotic resistance in H. pylori when applied to strains or directly to gastric biopsy specimens.
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