Abstract
“Heteroresistance” is a widely applied term that characterizes most of the multidrug-resistant microorganisms. In microbiological practice, the word “heteroresistance” indicates diverse responses to specific antibiotics by bacterial subpopulations in the same patient. These resistant subpopulations of heteroresistant strains do not respond to antibiotic therapy in vitro or in vivo. Presently, there is no standard protocol available for the treatment of infections caused by heteroresistant Helicobacter pylori in clinical settings, at least according to recent guidelines. Thus, there is a definite need to open a new discussion on how to recognize, how to screen, and how to eliminate those problematic strains in clinical and environmental samples. Since there is great interest in developing new strategies to improve the eradication rate of anti-H. pylori treatments, the presence of heteroresistant strains/clones among clinical isolates of the bacteria should be taken into account. Indeed, increased knowledge of gastroenterologists about the existence of heteroresistance phenomena is highly required. Moreover, the accurate breakpoints should be examined/determined in order to have a solid statement of heteroresistance among the H. pylori isolates. The primary definition of heteroresistance was about coexistence of both resistant and susceptible isolates at the similar gastric microniche at once, while we think that it can be happened subsequently as well. The new guidelines should include a personalized aspect in the standard protocol to select a precise, effective antibiotic therapy for infected patients and also address the problems of regional antibiotic susceptibility profiles.
Introduction
Helicobacter pylori (H. pylori) is a Gram-negative and transmissible microorganism that resides in the deep gastric mucosa of humans. Current estimation of people infected with this microorganism is around 4.4 billion of the world’s population (Kusters et al., 2006). The infection causes serious digestive disease such as chronic gastritis, peptic ulcer disease (PUD), and gastric cancer in 1–10% of colonized individuals (Blaser, 1990, 1992; Parsonnet et al., 1991; Atherton, 2006). It is also suspected of inducing or worsening Parkinson’s disease (Dobbs et al., 2016). For reasons that are unclear, many of the colonized persons remain asymptomatic for their whole life (Malfertheiner et al., 2018b). Treating H. pylori infection induces the regression of mucosa-associated lymphoid tissue (MALT) lymphoma and has recently been considered as a preventive approach for the management of gastric cancer (Bayerdörffer et al., 1995; Wong et al., 2004; Atherton, 2006). The elimination of this pathogen is also reducing or eliminating Parkinson’s disease symptoms (Liu et al., 2017). Many guidelines have been established that outline a number of therapeutic regimens to provide optimal treatments using conventional antibiotics and proton pump inhibitors (PPIs). However, the lack of an ideal therapy is still a major challenge in H. pylori-related treatment. Apart from the many antibiotics applied to fight the infection, a skyrocketing increase in antimicrobial resistance is hampering the elimination of H. pylori (Chiba et al., 1992; Gao et al., 2010). Although patient compliance and other environmental factors are partially involved, antibiotic resistance is mainly responsible for H. pylori treatment failures (Graham, 1998; Björkholm et al., 2001; De Francesco et al., 2010; Graham and Fischbach, 2010; Thung et al., 2016). Prevalence of antibiotic resistance among H. pylori strains varies in different geographic areas (Björkholm et al., 2001; Glupczynski et al., 2001; Megraud, 2004; Fischbach and Evans, 2007; Gao et al., 2010; Megraud et al., 2012; Khaiboullina et al., 2016). This global problem has triggered a universal drive to find a better solution. Following the rapid increase in resistance rates for conventional antibiotics used for eliminating H. pylori, many studies showed failures of first, second, and third lines of treatments (Wolle et al., 2002; Zullo et al., 2007; Kim et al., 2011; Oleastro et al., 2011; Saracino et al., 2012; Tonkic et al., 2012; Hsiang et al., 2013; Maleknejad et al., 2015; Kori et al., 2017; Macias-Garcia et al., 2017). The ultimate goal in therapeutic regimens against H. pylori is to achieve more than 90% eradication rate, which has currently proved unreachable (Zagari et al., 2018). Most recent worldwide reports together with meta-analyses indicate that the efficacy of antibiotics available to treat H. pylori infections has been significantly reduced (Figueiredo et al., 2005; Suzuki and Mori, 2018). In addition, emergence of multidrug-resistant H. pylori strains has been devastating for clinicians and microbiologists aiming to eliminate this infection (Kwon et al., 2003; Boyanova, 2009). The situation is made worse by the lack of a vaccine against H. pylori (Luo et al., 2018; Pan et al., 2018; Malfertheiner et al., 2018a,b). Now that antibiotic resistance has been recognized as a growing problem in the treatment of H. pylori infection, a much less investigated phenomenon among bacteria, namely, “heteroresistance” should be addressed. An understanding of the causes of increasing prevalence of resistant strains or, in other words, heteroresistant strains, could be pivotal in the design of effective guidelines both on national and international scales. In this paper, we discuss first the general concept of heteroresistance reported for some H. pylori strains; second, we will compare this resistance to co-infection with this bacterium. Ultimately, we hope for a reformulation of the treatment options of antibiotic-resistant H. pylori infections.
The phenomenon of heteroresistance is based on the growth differences in bacterial subpopulations within the same strain in response to a particular antibiotic (El-Halfawy and Valvano, 2013; Wang et al., 2014; El-Halfawy and Valvano, 2015). “Heteroresistance” can be one of several terms applied to multidrug-resistant microorganisms (Alam et al., 2001; Wannet, 2002; Plipat et al., 2005; Matteo et al., 2006; Hawley et al., 2008; Goldman et al., 2014; He et al., 2017). Heteroresistant clones are able to survive in the presence of antibiotics in both in vitro and in vivo microniches (Yeldandi et al., 1988; Gillespie, 2002; Ribes et al., 2010; Russo et al., 2011). Due to the lack of standard methods of characterizing heteroresistance, its detection is poor (Hofmann-Thiel et al., 2009; Huang et al., 2010; Goldman et al., 2014; He et al., 2017). The first heteroresistant Gram-negative bacterium, Haemophilus influenzae, was discovered in 1947 (Alexander and Leidy, 1947). Since then, not many bacteria have been listed as heteroresistant, even though this phenomenon is widely spread across many bacterial species. The Clinical and Laboratory Standards Institute (CLSI), one of several international bodies dealing with antimicrobial resistances, has published many reports determining resistant, sensitive, and intermediately resistant organisms. However, there is no established definition of heteroresistant strains (Osato et al., 2001; El-Halfawy and Valvano, 2015). Additionally, practitioners are not fully aware of the frequency and clinical activity of heteroresistant isolates. Therefore, the focus of this paper is to pinpoint the clinical impact of H. pylori heteroresistant strains and to highlight the urgent need for revised guidelines to manage and cure this infection.
Heteroresistant H. Pylori
The emergence of heteroresistance in H. pylori resistant strains has never been discussed in published guidelines (Malfertheiner et al., 2007, 2012; Graham and Shiotani, 2008; Fock et al., 2013; Subspecialty Group of Gastroenterology, 2015; Sugano et al., 2015; Zagari et al., 2015; Chey et al., 2017; Mahachai et al., 2017; Smith et al., 2017). Matteo et al. found two H. pylori strains that significantly differed in antibiotic sensitivity even though they were obtained from two antral biopsies isolated from a single patient (Matteo et al., 2008). The minimum inhibitory concentration (MIC) for amoxicillin in those strains varied between 2 and 0.06 μg/ml, respectively. This finding brings a new insight about the importance of heteroresistant strains and the need for their detection prior to antibiotic prescription. The important clinical consequence of the existence of heteroresistant H. pylori strains is the possibility of their further propagation despite antibiotic therapy. The absence of an accurate and rigorous approach hampers the exact determination of the real prevalence of these strains in the affected individuals. Additionally, data about persistence or virulence of these heteroresistant bacteria are currently lacking (El-Halfawy and Valvano, 2013; Didelot et al., 2016; Halaby et al., 2016). In consideration of the likely failure of treatment of heteroresistant strains, the rapid increase of gastroduodenal diseases is both predictable and expected. Consequently, the high potential of heterogeneity reported for this bacterium must be thoroughly researched (Yamaoka, 2012).
Heteroresistant Strains Versus Co-Infections
There is a common belief among microbiologists about the existence of two or more different H. pylori strains colonizing the same human stomach (Jorgensen et al., 1996; Kersulyte et al., 1999; Lai et al., 2016; Mansour et al., 2016; Raymond et al., 2016). It seems that following bacterial colonization of our stomach, H. pylori is able to use its remarkable genetic variability to create new variants (Jiang et al., 1996; Gottke et al., 2000; Spechler et al., 2000; Suerbaum, 2000; Gravina et al., 2016). Given the large potential of H. pylori in generating new genetically diverse isolates, the co-infections theory, in our opinion, needs to be updated by the incorporation of the heteroresistance concept. According to the theory of heteroresistance, human gastric mucosa can be a territory for both resistant and sensitive H. pylori strains exposed to specific antibiotics while the origin of isolates remains identical. During infections, approximately 5% of them are actually mixed infections caused by independent H. pylori strains. As such, evolved pathogen population is composed of both genetically identical and different strains (Lai et al., 2016). It is important to investigate if heteroresistant strains affect the final outcome (severe or mild diseases) of this infection or not. Additionally, the exact prevalence of co-infections and heteroresistance in vivo should be investigated in greater detail in future studies. Clearly, both phenotypical and genotypical analyses are required to answer this difficult question.
An Explanation for Inconsistent Findings in in vitro and in vivo Experiments
Currently, we are still far from understanding the exact mechanisms involved in the development of this less-recognized biologic action among the bacteria. Clinicians are well aware of inconsistencies between in vitro and in vivo susceptibility tests (Glupczynski, 1993; Best et al., 1997; Loo et al., 1997; Bereswill et al., 1999; Chatsuwan and Amyes, 1999; van der Voort et al., 2000; Gonzalez et al., 2001; Warburton-Timms and McNulty, 2001; Adeniyi et al., 2009). Unfortunately, there is no universally standard method to determine MIC for H. pylori species. We suggest that heteroresistance is a likely cause of this inconsistency. Our main evidence for this claim is the concept of the simultaneous presence of various H. pylori genotypes in the human stomach that are associated with different susceptibility profiles (Kim et al., 2003; Graham and Fischbach, 2010; Lee et al., 2014). Because independent subpopulations of H. pylori are growing rapidly, we detect numerous different isolates with confusing susceptibility patterns originating from the same patient. Propagation of various H. pylori isolates in vitro can lead to conflicting results of antibiotic susceptibility testing. Thus heteroresistance is a major clinical issue, which should attract very intense attention in the upcoming years.
New Guideline Against H. Pylori?
Similar to other bacterial infections, H. pylori management was a challenging area of the research for decades after its discovery (Malfertheiner et al., 2007, 2012; Subspecialty Group of Gastroenterology, 2015; Zagari et al., 2015; Isaeva et al., 2016; Authors, Responsible in representation of the DGVS, 2017; Chey et al., 2017; Mahachai et al., 2017; Smith et al., 2017). As far as diagnosis is concerned, there is reasonable consensus between scientists. However, there is absolutely no agreement on the optimal therapeutic intervention especially in the case of first-line treatment (Chey et al., 2007; Malfertheiner et al., 2007, 2012, 2017; Asaka et al., 2010). Overall, the mechanisms of resistance to all antibiotics used against H. pylori are well known (Debets-Ossenkopp et al., 1996; Burns et al., 1998; Megraud, 1998, 2003; van der Wouden et al., 2001; Keating, 2013). The current body of evidence is based on the fact that many antibiotic therapy failures are the result of genetic variations among the different H. pylori isolates that cause mixed infections in a host. The open question, however, is about the impact of heteroresistance on the development of severe gastroduodenal disorders in infected patients. Indeed, a long list of experiments is necessary to pinpoint the actual role of heteroresistance in the development of H. pylori persistent infections. Thus, updated guidelines would lead to a more effective cure if they would consider the practical approaches in dealing with heteroresistant strains. As such, this paper can be useful in the preparation for next Maastricht meetings aimed to enrich the content of current guidelines with the concept of heteroresistant H. pylori strains.
Future Perspectives of H. Pylori Treatment
Antibiotic resistance among clinical H. pylori isolates is rapidly disseminating worldwide and we have to think deeply how to better manage it. At present, low doses of prescribed antibiotics, slow bacterial growth rate, bacterial coccoid forms, and genetic mutations in H. pylori are the major reasons for antibiotic resistance reported so far. Research into the presence of heteroresistance isolates of this bacterium been sorely neglected. Integration of heteroresistance phenomenon in H. pylori in clinical treatment decisions is essential. The primary definition of heteroresistance was about coexistence of both resistant and susceptible isolates at the similar gastric microniche at once, while we think that it can be happened subsequently as well. Currently, there are no data describing in detail the heteroresistant H. pylori strains, which reduces the usefulness of the current guidelines. We firmly believe that this is the time to improve our understanding of the heteroresistance phenomena and incorporate this into uniform guidelines. Furthermore, there is a definite need to initiate discussions and learn how to recognize, manage, screen, and eliminate these infectious strains from clinics and the environment. Undoubtedly, there is an urgent necessity for new guidelines describing the heteroresistance phenomena of H. pylori strains.
Conclusion
To the best of our knowledge, this is the first paper suggest new challenge for designing the new useful guideline according to the evidence-based findings about the antibiotic resistance. Indeed, increased knowledge of gastroenterologists about the existence of heteroresistance phenomena is highly required. Moreover, the accurate breakpoints should be examined/determined in order to have a solid statement of heteroresistance among the H. pylori isolates.
Statements
Author contributions
All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.
Funding
AR was supported by state assignments 20.5175.2017/6.7 and 17.9783.2017/8.9 of the Ministry of Science and Higher Education of the Russian Federation.
Acknowledgments
The contents of the paper are the sole responsibility of the authors and do not necessarily represent the official views of any institute or organization.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
1
AdeniyiC. B.LawalT. O.MahadyG. B. (2009). In vitro susceptibility of Helicobacter pylori to extracts of Eucalyptus camaldulensis and Eucalyptus torelliana. Pharm. Biol.47, 99–102. doi: 10.1080/13880200802448708
2
AlamM. R.DonabedianS.BrownW.GordonJ.ChowJ. W.ZervosM. J.et al. (2001). Heteroresistance to vancomycin in Enterococcus faecium. J. Clin. Microbiol.39, 3379–3381. doi: 10.1128/JCM.39.9.3379-3381.2001
3
AlexanderH. E.LeidyG. (1947). Mode of action of streptomycin on type b Haemophilus influenzae. J. Exp. Med.85, 607–621. doi: 10.1084/jem.85.6.607
4
AsakaM.KatoM.TakahashiS.FukudaY.SugiyamaT.OtaH.et al. (2010). Guidelines for the management of Helicobacter pylori infection in Japan: 2009 revised edition. Helicobacter15, 1–20. doi: 10.1111/j.1523-5378.2009.00738.x
5
AthertonJ. C. (2006). The pathogenesis of Helicobacter pylori-induced gastro-duodenal diseases. Annu. Rev. Pathol. Mech. Dis.1, 63–96. doi: 10.1146/annurev.pathol.1.110304.100125
6
Authors, Responsible in representation of the DGVS (2017). S2k-Guideline Helicobacter pylori and gastroduodenal ulcer disease. Z. Gastroenterol.55, 167–206. doi: 10.1055/s-0042-119653
7
BayerdörfferE.RudolphB.NeubauerA.ThiedeC.LehnN.EidtS.et al. (1995). Regression of primary gastric lymphoma of mucosa-associated lymphoid tissue type after cure of Helicobacter pylori infection. Lancet345, 1591–1594. doi: 10.1016/S0140-6736(95)90113-2
8
BereswillS.VeyT.KistM. (1999). Susceptibility in vitro of Helicobacter pylori to cetylpyridinium chloride. FEMS Immunol. Med. Microbiol.24, 189–192. doi: 10.1111/j.1574-695X.1999.tb01281.x
9
BestL. M.HaldaneD. J.BezansonG. S.Veldhuyzen van ZantenS. J. (1997). Helicobacter pylori: primary susceptibility to clarithromycin in vitro in Nova Scotia. Can. J. Gastroenterol.11, 298–300. doi: 10.1155/1997/159637
10
BjörkholmB.SjölundM.FalkP. G.BergO. G.EngstrandL.AnderssonD. I. (2001). Mutation frequency and biological cost of antibiotic resistance in Helicobacter pylori. Proc. Natl. Acad. Sci.98, 14607–14612. doi: 10.1073/pnas.241517298
11
BlaserM. J. (1990). Helicobacter pylori and the pathogenesis of gastroduodenal inflammation. J. Infect. Dis.161, 626–633. doi: 10.1093/infdis/161.4.626
12
BlaserM. J. (1992). Hypotheses on the pathogenesis and natural history of Helicobacter pylori-induced inflammation. Gastroenterology102, 720–727. doi: 10.1016/0016-5085(92)90126-J
13
BoyanovaL. (2009). Prevalence of multidrug-resistant Helicobacter pylori in Bulgaria. J. Med. Microbiol.58, 930–935. doi: 10.1099/jmm.0.009993-0
14
BurnsB. P.MendzG. L.HazellS. L. (1998). A novel mechanism for resistance to the antimetabolite N-phosphonoacetyl-L-aspartate by Helicobacter pylori. J. Bacteriol.180, 5574–5579. PMID:
15
ChatsuwanT.AmyesS. G. (1999). Setting the standard for determining the in-vitro susceptibility of Helicobacter pylori to metronidazole. J. Antimicrob. Chemother.44, 291–293. doi: 10.1093/jac/44.2.291a
16
CheyW. D.LeontiadisG. I.HowdenC. W.MossS. F. (2017). ACG clinical guideline: treatment of Helicobacter pylori infection. Am. J. Gastroenterol.112, 212–239. doi: 10.1038/ajg.2016.563
17
CheyW. D.WongB. C.Practice Parameters Committee of the American College of Gastroenterology (2007). American College of gastroenterology guideline on the management of Helicobacter pylori infection. Am. J. Gastroenterol.102, 1808–1825. doi: 10.1111/j.1572-0241.2007.01393.x
18
ChibaN.RaoB. V.RademakerJ. W.HuntR. H. (1992). Meta-analysis of the efficacy of antibiotic therapy in eradicating Helicobacter pylori. Am. J. Gastroenterol.87, 1716–1727.
19
De FrancescoV.GiorgioF.HassanC.ManesG.VannellaL.PanellaC.et al. (2010). Worldwide H. pylori antibiotic resistance: a systematic review. J. Gastrointestin. Liver Dis.19, 409–414.
20
Debets-OssenkoppY. J.SparriusM.KustersJ. G.KolkmanJ. J.Vandenbroucke-GraulsC. M. (1996). Mechanism of clarithromycin resistance in clinical isolates of Helicobacter pylori. FEMS Microbiol. Lett.142, 37–42. doi: 10.1111/j.1574-6968.1996.tb08404.x
21
DidelotX.WalkerA. S.PetoT. E.CrookD. W.WilsonD. J. (2016). Within-host evolution of bacterial pathogens. Nat. Rev. Microbiol.14, 150–162. doi: 10.1038/nrmicro.2015.13
22
DobbsS. M.DobbsR. J.WellerC.CharlettA.AugustinA.TaylorD.et al. (2016). Peripheral aetiopathogenic drivers and mediators of Parkinson’s disease and co-morbidities: role of gastrointestinal microbiota. J. Neurovirol.22, 22–32. doi: 10.1007/s13365-015-0357-8
23
El-HalfawyO. M.ValvanoM. A. (2013). Chemical communication of antibiotic resistance by a highly resistant subpopulation of bacterial cells. PLoS One8:e68874. doi: 10.1371/journal.pone.0068874
24
El-HalfawyO. M.ValvanoM. A. (2015). Antimicrobial heteroresistance: an emerging field in need of clarity. Clin. Microbiol. Rev.28, 191–207. doi: 10.1128/CMR.00058-14
25
FigueiredoC.MachadoJ. C.YamaokaY. (2005). Pathogenesis of Helicobacter pylori infection. Helicobacter10, 14–20. doi: 10.1111/j.1523-5378.2005.00339.x
26
FischbachL.EvansE. (2007). Meta-analysis: the effect of antibiotic resistance status on the efficacy of triple and quadruple first-line therapies for Helicobacter pylori. Aliment. Pharmacol. Ther.26, 343–357. doi: 10.1111/j.1365-2036.2007.03386.x
27
FockK. M.GrahamD. Y.MalfertheinerP. (2013). Helicobacter pylori research: historical insights and future directions. Nat. Rev. Gastroenterol. Hepatol.10, 495–500. doi: 10.1038/nrgastro.2013.96
28
GaoW.ChengH.HuF.LiJ.WangL.YangG.et al. (2010). The evolution of Helicobacter pylori antibiotics resistance over 10 years in Beijing, China. Helicobacter15, 460–466. doi: 10.1111/j.1523-5378.2010.00788.x
29
GillespieS. H. (2002). Evolution of drug resistance in Mycobacterium tuberculosis: clinical and molecular perspective. Antimicrob. Agents Chemother.46, 267–274. doi: 10.1128/AAC.46.2.267-274.2002
30
GlupczynskiY. (1993). In vitro susceptibility testing of Helicobacter pylori to antimicrobial agents: basis for treatment or microbiologists’ obsession?Zentralbl. Bakteriol.280, 227–238. doi: 10.1016/S0934-8840(11)80960-6
31
GlupczynskiY.MegraudF.Lopez-BreaM.AndersenL. (2001). European multicentre survey of in vitro antimicrobial resistance in Helicobacter pylori. Eur. J. Clin. Microbiol. Infect. Dis.20, 820–823. doi: 10.1007/s100960100611
32
GoldmanJ. L.HarrisonC. J.MyersA. L.JacksonM. A.SelvaranganR. (2014). No evidence of vancomycin minimal inhibitory concentration creep or heteroresistance identified in pediatric Staphylococcus aureus blood isolates. Pediatr. Infect. Dis. J.33, 216–218. doi: 10.1097/01.inf.0000436281.18687.0c
33
GonzalezC.GarciaA.DarochF.KawaguchiF.SolarH.RiveraN.et al. (2001). In vitro antimicrobial susceptibility of Helicobacter pylori strains: isolation of strains resistant to clarithromycin. Rev. Med. Chil.129, 643–646. PMID:
34
GottkeM. U.FalloneC. A.BarkunA. N.VogtK.LooV.TrautmannM.et al. (2000). Genetic variability determinants of Helicobacter pylori: influence of clinical background and geographic origin of isolates. J. Infect. Dis.181, 1674–1681. doi: 10.1086/315425
35
GrahamD. Y. (1998). Antibiotic resistance in Helicobacter pylori: implications for therapy. Gastroenterology115, 1272–1277.
36
GrahamD. Y.FischbachL. (2010). Helicobacter pylori treatment in the era of increasing antibiotic resistance. Gut59, 1143–1153. doi: 10.1136/gut.2009.192757
37
GrahamD. Y.ShiotaniA. (2008). Newer concepts regarding resistance in the treatment Helicobacter pylori infections. Nat. Clin. Pract. Gastroenterol. Hepatol.5, 321–331. doi: 10.1038/ncpgasthep1138
38
GravinaA.FedericoA.DallioM.SgambatoD.MirandaA.TuccilloC. (2016). Intrafamilial spread of Helicobacter pylori infection. J. Gastroen. Hepatol. Endosc.1:1003.
39
HalabyT.KucukkoseE.JanssenA. B.RogersM. R.DoorduijnD. J.van der ZandenA. G.et al. (2016). Genomic characterization of colistin heteroresistance in Klebsiella pneumoniae during a nosocomial outbreak. Antimicrob. Agents Chemother.60, 6837–6843. doi: 10.1128/AAC.01344-16
40
HawleyJ. S.MurrayC. K.JorgensenJ. H. (2008). Colistin heteroresistance in acinetobacter and its association with previous colistin therapy. Antimicrob. Agents Chemother.52, 351–352. doi: 10.1128/AAC.00766-07
41
HeJ.JiaX.YangS.XuX.SunK.LiC.et al. (2017). Heteroresistance to carbapenems in invasive Pseudomonas aeruginosa infections. Int. J. Antimicrob. Agents29, 552–559. doi: 10.1016/j.ijantimicag.2017.10.014
42
Hofmann-ThielS.van IngenJ.FeldmannK.TuraevL.UzakovaG. T.MurmusaevaG.et al. (2009). Mechanisms of heteroresistance to isoniazid and rifampin of Mycobacterium tuberculosis in Tashkent, Uzbekistan. Eur. Respir. J.33, 368–374. doi: 10.1183/09031936.00089808
43
HsiangJ.SelvaratnamS.TaylorS.YeohJ.TanY. M.HuangJ.et al. (2013). Increasing primary antibiotic resistance and ethnic differences in eradication rates of Helicobacter pylori infection in New Zealand--a new look at an old enemy. N. Z. Med. J.126, 64–76. PMID:
44
HuangH.WeintraubA.FangH.WuS.ZhangY.NordC. E. (2010). Antimicrobial susceptibility and heteroresistance in Chinese Clostridium difficile strains. Anaerobe16, 633–635. doi: 10.1016/j.anaerobe.2010.09.002
45
IsaevaG.VakatovaL.EfimovaN.RizvanovA.ValiullinaI. (2016). Gastric microbiota and morphological changes of the gastroduodenal tract associated with Helicobacter pylori Infection. Bionanoscience6, 483–486. doi: 10.1007/s12668-016-0260-7
46
JiangQ.HiratsukaK.TaylorD. E. (1996). Variability of gene order in different Helicobacter pylori strains contributes to genome diversity. Mol. Microbiol.20, 833–842.
47
JorgensenM.DaskalopoulosG.WarburtonV.MitchellH. M.HazellS. L. (1996). Multiple strain colonization and metronidazole resistance in Helicobacter pylori-infected patients: identification from sequential and multiple biopsy specimens. J. Infect. Dis.174, 631–635. doi: 10.1093/infdis/174.3.631
48
KeatingT. A. (2013). Resistance mechanism to an uncompetitive inhibitor of a single-substrate, single-product enzyme: a study of Helicobacter pylori glutamate racemase. Future Med. Chem.5, 1203–1214. doi: 10.4155/fmc.13.94
49
KersulyteD.ChalkauskasH.BergD. E. (1999). Emergence of recombinant strains of Helicobacter pylori during human infection. Mol. Microbiol.31, 31–43.
50
KhaiboullinaS. F.AbdulkhakovS.KhalikovaA.SafinaD.MartynovaE. V.DavidyukY.et al. (2016). Serum cytokine signature that discriminates Helicobacter pylori positive and negative juvenile gastroduodenitis. Front. Microbiol.7:1916. doi: 10.3389/fmicb.2016.01916
51
KimJ. J.KimJ. G.KwonD. H. (2003). Mixed-infection of antibiotic susceptible and resistant Helicobacter pylori isolates in a single patient and underestimation of antimicrobial susceptibility testing. Helicobacter8, 202–206. doi: 10.1046/j.1523-5378.2003.00145.x
52
KimJ. Y.KimN.ParkH. K.JoH. J.ShinC. M.LeeS. H.et al. (2011). Primary antibiotic resistance of Helicobacter pylori strains and eradication rate according to gastroduodenal disease in Korea. Korean J. Gastroenterol.58, 74–81. doi: 10.4166/kjg.2011.58.2.74
53
KoriM.YahavJ.BerdinsteinR.ShmuelyH. (2017). Primary and secondary antibiotic resistance of Helicobacter pylori in Israeli children and adolescents. Isr. Med. Assoc. J.19, 747–750. PMID:
54
KustersJ. G.van VlietA. H.KuipersE. J. (2006). Pathogenesis of Helicobacter pylori infection. Clin. Microbiol. Rev.19, 449–490. doi: 10.1128/CMR.00054-05
55
KwonD. H.DoreM.KimJ.KatoM.LeeM.WuJ.et al. (2003). High-level β-lactam resistance associated with acquired multidrug resistance in Helicobacter pylori. Antimicrob. Agents Chemother.47, 2169–2178. doi: 10.1128/AAC.47.7.2169-2178.2003
56
LaiC.-H.HuangJ.-C.Chiang-NiC.LiJ.-P.WuL.-T.WuH.-S.et al. (2016). Mixed infections of Helicobacter pylori isolated from patients with gastrointestinal diseases in Taiwan. Gastroenterol. Res. Pract.2016:7521913. doi: 10.1155/2016/7521913
57
LeeJ. Y.KimN.KimM. S.ChoiY. J.LeeJ. W.YoonH.et al. (2014). Factors affecting first-line triple therapy of Helicobacter pylori including CYP2C19 genotype and antibiotic resistance. Dig. Dis. Sci.59, 1235–1243. doi: 10.1007/s10620-014-3093-7
58
LiuH.SuW.LiS.DuW.MaX.JinY.et al. (2017). Eradication of Helicobacter pylori infection might improve clinical status of patients with Parkinson’s disease, especially on bradykinesia. Clin. Neurol. Neurosurg.160, 101–104. doi: 10.1016/j.clineuro.2017.07.003
59
LooV. G.FalloneC. A.De SouzaE.LavalleeJ.BarkunA. N. (1997). In-vitro susceptibility of Helicobacter pylori to ampicillin, clarithromycin, metronidazole and omeprazole. J. Antimicrob. Chemother.40, 881–883. doi: 10.1093/jac/40.6.881
60
LuoS.LiuW.ZengZ.YeF.HuC.XuN.et al. (2018). Toxic adjuvants alter the function and phenotype of dendritic cells to initiate adaptive immune responses induced by oral Helicobacter pylori vaccines. Helicobacter23:e12536. doi: 10.1111/hel.12536
61
Macias-GarciaF.Llovo-TaboadaJ.Diaz-LopezM.Baston-ReyI.Dominguez-MunozJ. E. (2017). High primary antibiotic resistance of Helicobacter Pylori strains isolated from dyspeptic patients: a prevalence cross-sectional study in Spain. Helicobacter22:e12440. doi: 10.1111/hel.12440
62
MahachaiV.VilaichoneR. K.PittayanonR.RojborwonwitayaJ.LeelakusolvongS.ManeerattanapornM.et al. (2017). H. pylori management in ASEAN: the Bangkok Consensus Report. J. Gastroenterol. Hepatol.33, 37–56. doi: 10.1111/jgh.13911
63
MaleknejadS.MojtahediA.Safaei-AslA.TaghaviZ.KazemnejadE. (2015). Primary antibiotic resistance to Helicobacter pylori strains isolated from children in Northern Iran: a single center study. Iran. J. Pediatr.25:e2661. doi: 10.5812/ijp.2661
64
MalfertheinerP.MegraudF.O’MorainC.BazzoliF.El-OmarE.GrahamD.et al. (2007). Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus Report. Gut56, 772–781. doi: 10.1136/gut.2006.101634
65
MalfertheinerP.MegraudF.O’MorainC. A.GisbertJ. P.KuipersE. J.AxonA. T.et al. (2017). Management of Helicobacter pylori infection—the Maastricht V/florence consensus report. Gut66, 772–781. doi: 10.1136/gutjnl-2016-312288
66
MalfertheinerP.MegraudF.O’morainC. A.AthertonJ.AxonA. T.BazzoliF.et al. (2012). Management of Helicobacter pylori infection—the Maastricht IV/florence consensus report. Gut61, 646–664. doi: 10.1136/gutjnl-2012-302084
67
MalfertheinerP.SelgradM.WexT.RomiB.BorgogniE.SpensieriF.et al. (2018a). Efficacy, immunogenicity, and safety of a parenteral vaccine against Helicobacter pylori in healthy volunteers challenged with a Cag-positive strain: a randomised, placebo-controlled phase 1/2 study. Lancet Gastroenterol. Hepatol.3, 698–707. doi: 10.1016/S2468-1253(18)30125-0
68
MalfertheinerP.VeneritoM.SchulzC. (2018b). Helicobacter pylori Infection: new facts in clinical management. Curr. Treat. Options Gastroenterol.16, 605–615. doi: 10.1007/s11938-018-0209-8
69
MansourK. B.FendriC.BattikhH.GarnierM.ZribiM.JliziA.et al. (2016). Multiple and mixed Helicobacter pylori infections: comparison of two epidemiological situations in Tunisia and France. Infect. Genet. Evol.37, 43–48. doi: 10.1016/j.meegid.2015.10.028
70
MatteoM. J.GranadosG.OlmosM.WonagaA.CatalanoM. (2008). Helicobacter pylori amoxicillin heteroresistance due to point mutations in PBP-1A in isogenic isolates. J. Antimicrob. Chemother.61, 474–477. doi: 10.1093/jac/dkm504
71
MatteoM. J.PerezC. V.DomingoM. R.OlmosM.SanchezC.CatalanoM. (2006). DNA sequence analysis of rdxA and frxA from paired metronidazole-sensitive and -resistant Helicobacter pylori isolates obtained from patients with heteroresistance. Int. J. Antimicrob. Agents27, 152–158. doi: 10.1016/j.ijantimicag.2005.09.019
72
MegraudF. (1998). Epidemiology and mechanism of antibiotic resistance in Helicobacter pylori. Gastroenterology115, 1278–1282. doi: 10.1016/S0016-5085(98)70101-5
73
MegraudF. (2003). Helicobacter pylori resistance to antibiotics: prevalence, mechanism, detection. What’s new?Can. J. Gastroenterol.17(Suppl. B), 49B–52B. doi: 10.1155/2003/704035
74
MegraudF. (2004). H pylori antibiotic resistance: prevalence, importance, and advances in testing. Gut53, 1374–1384. doi: 10.1136/gut.2003.022111
75
MegraudF.CoenenS.VersportenA.KistM.Lopez-BreaM.HirschlA. M.et al. (2012). Helicobacter pylori resistance to antibiotics in Europe and its relationship to antibiotic consumption. Gut62, 34–42. doi: 10.1136/gutjnl-2012-302254
76
OleastroM.CabralJ.RamalhoP. M.LemosP. S.PaixaoE.BenolielJ.et al. (2011). Primary antibiotic resistance of Helicobacter pylori strains isolated from Portuguese children: a prospective multicentre study over a 10 year period. J. Antimicrob. Chemother.66, 2308–2311. doi: 10.1093/jac/dkr293
77
OsatoM. S.ReddyR.ReddyS. G.PenlandR. L.GrahamD. Y. (2001). Comparison of the Etest and the NCCLS-approved agar dilution method to detect metronidazole and clarithromycin resistant Helicobacter pylori. Int. J. Antimicrob. Agents17, 39–44. doi: 10.1016/S0924-8579(00)00320-4
78
PanX.KeH.NiuX.LiS.LvJ.PanL. (2018). Protection against Helicobacter pylori infection in BalB/c mouse model by oral administration of multivalent epitope-based vaccine of cholera Toxin B subunit-hUUc. Front. Immunol.9. doi: 10.3389/fimmu.2018.01003
79
ParsonnetJ.FriedmanG. D.VandersteenD. P.ChangY.VogelmanJ. H.OrentreichN.et al. (1991). Helicobacter pylori infection and the risk of gastric carcinoma. N. Engl. J. Med.325, 1127–1131. doi: 10.1056/NEJM199110173251603
80
PlipatN.LivniG.BertramH.ThomsonR. B.Jr. (2005). Unstable vancomycin heteroresistance is common among clinical isolates of methiciliin-resistant Staphylococcus aureus. J. Clin. Microbiol.43, 2494–2496. doi: 10.1128/JCM.43.5.2494-2496.2005
81
RaymondJ.ThibergeJ. M.DaugaC. (2016). Diagnosis of Helicobacter pylori recurrence: relapse or reinfection? Usefulness of molecular tools. Scand. J. Gastroenterol.51, 672–678. doi: 10.3109/00365521.2015.1132338
82
RibesS.Pachón-IbáñezM.DomínguezM.FernándezR.TubauF.ArizaJ.et al. (2010). In vitro and in vivo activities of linezolid alone and combined with vancomycin and imipenem against Staphylococcus aureus with reduced susceptibility to glycopeptides. Eur. J. Clin. Microbiol. Infect. Dis.29, 1361–1367. doi: 10.1007/s10096-010-1007-y
83
RussoT. A.PageM. G.BeananJ. M.OlsonR.HujerA. M.HujerK. M.et al. (2011). In vivo and in vitro activity of the siderophore monosulfactam BAL30072 against Acinetobacter baumannii. J. Antimicrob. Chemother.66, 867–873. doi: 10.1093/jac/dkr013
84
SaracinoI. M.ZulloA.HoltonJ.CastelliV.FioriniG.ZaccaroC.et al. (2012). High prevalence of primary antibiotic resistance in Helicobacter pylori isolates in Italy. J. Gastrointestin. Liver Dis.21, 363–365.
85
SmithS.BoyleB.BrennanD.BuckleyM.CrottyP.DoyleM.et al. (2017). The Irish Helicobacter pylori working group consensus for the diagnosis and treatment of H. pylori infection in adult patients in Ireland. Eur. J. Gastroenterol. Hepatol. doi: 10.1097/MEG.0000000000000822
86
SpechlerS. J.FischbachL.FeldmanM. (2000). Clinical aspects of genetic variability in Helicobacter pylori. JAMA283, 1264–1266. doi: 10.1001/jama.283.10.1264
87
Subspecialty Group of Gastroenterology, t.S.o.P.C.M.A (2015). Guidelines for Helicobacter pylori infection in children in China. Zhonghua Er Ke Za Zhi53, 496–498. PMID:
88
SuerbaumS. (2000). Genetic variability within Helicobacter pylori. Int. J. Med. Microbiol.290, 175–181. doi: 10.1016/S1438-4221(00)80087-9
89
SuganoK.TackJ.KuipersE. J.GrahamD. Y.El-OmarE. M.MiuraS.et al. (2015). Kyoto global consensus report on Helicobacter pylori gastritis. Gut64, 1353–1367. doi: 10.1136/gutjnl-2015-309252
90
SuzukiH.MoriH. (2018). World trends for H. pylori eradication therapy and gastric cancer prevention strategy by H. pylori test-and-treat. J. Gastroenterol.53, 354–361. doi: 10.1007/s00535-017-1407-1
91
ThungI.AraminH.VavinskayaV.GuptaS.ParkJ.CroweS.et al. (2016). the global emergence of Helicobacter pylori antibiotic resistance. Aliment. Pharmacol. Ther.43, 514–533. doi: 10.1111/apt.13497
92
TonkicA.TonkicM.BrnicD.NovakA.PuljizZ.SimunicM. (2012). Time trends of primary antibiotic resistance of Helicobacter pylori isolates in Southern Croatia. J. Chemother.24, 182–184. doi: 10.1179/1973947812Y.0000000001
93
van der VoortP. H.van der HulstR. W.ZandstraD. F.van der EndeA.GeraedtsA. A.TytgatG. N. (2000). In vitro susceptibility of Helicobacter pylori to, and in vivo suppression by, antimicrobials used in selective decontamination of the digestive tract. J. Antimicrob. Chemother.46, 803–805. doi: 10.1093/jac/46.5.803
94
van der WoudenE. J.ThijsJ. C.KustersJ. G.van ZwetA. A.KleibeukerJ. H. (2001). Mechanism and clinical significance of metronidazole resistance in Helicobacter pylori. Scand. J. Gastroenterol. Suppl.234, 10–14.
95
WangX.KangY.LuoC.ZhaoT.LiuL.JiangX.et al. (2014). Heteroresistance at the single-cell level: adapting to antibiotic stress through a population-based strategy and growth-controlled interphenotypic coordination. MBio5, e00942–e00913. doi: 10.1128/mBio.00942-13
96
WannetW. (2002). Spread of an MRSA clone with heteroresistance to oxacillin in the Netherlands. Euro Surveill.7, 73–74. doi: 10.2807/esm.07.05.00367-en
97
Warburton-TimmsV. J.McNultyC. A. (2001). Role of screening agar plates for in vitro susceptibility testing of Helicobacter pylori in a routine laboratory setting. J. Clin. Pathol.54, 408–411. doi: 10.1136/jcp.54.5.408
98
WolleK.LeodolterA.MalfertheinerP.KonigW. (2002). Antibiotic susceptibility of Helicobacter pylori in Germany: stable primary resistance from 1995 to 2000. J. Med. Microbiol.51, 705–709. doi: 10.1099/0022-1317-51-8-705
99
WongB. C.-Y.LamS. K.WongW. M.ChenJ. S.ZhengT. T.FengR. E.et al. (2004). Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial. JAMA291, 187–194. doi: 10.1001/jama.291.2.187
100
YamaokaY. (2012). Pathogenesis of Helicobacter pylori-related gastroduodenal diseases from molecular epidemiological studies. Gastroenterol. Res. Pract.2012. doi: 10.1155/2012/371503
101
YeldandiV.StrodtmanR.LentinoJ. (1988). In-vitro and in-vivo studies of trimethoprim-sulphamethoxazole against multiple resistant Staphylococcus aureus. J. Antimicrob. Chemother.22, 873–880. doi: 10.1093/jac/22.6.873
102
ZagariR. M.RabittiS.EusebiL. H.BazzoliF. (2018). Treatment of Helicobacter pylori infection: a clinical practice update. Eur. J. Clin. Investig.48:e12857. doi: 10.1111/eci.12857
103
ZagariR. M.RomanoM.OjettiV.StockbruggerR.GulliniS.AnnibaleB.et al. (2015). Guidelines for the management of Helicobacter pylori infection in Italy: the III Working Group Consensus Report 2015. Dig. Liver Dis.47, 903–912. doi: 10.1016/j.dld.2015.06.010
104
ZulloA.PernaF.HassanC.RicciC.SaracinoI.MoriniS.et al. (2007). Primary antibiotic resistance in Helicobacter pylori strains isolated in northern and central Italy. Aliment. Pharmacol. Ther.25, 1429–1434. doi: 10.1111/j.1365-2036.2007.03331.x
Summary
Keywords
Helicobacter pylori, heteroresistance, antibiotic resistance, guidelines, antibiotic therapy
Citation
Rizvanov AA, Haertlé T, Bogomolnaya L and Talebi Bezmin Abadi A (2019) Helicobacter pylori and Its Antibiotic Heteroresistance: A Neglected Issue in Published Guidelines. Front. Microbiol. 10:1796. doi: 10.3389/fmicb.2019.01796
Received
12 April 2019
Accepted
22 July 2019
Published
13 August 2019
Volume
10 - 2019
Edited by
Ghassan M. Matar, American University of Beirut, Lebanon
Reviewed by
Jose Ruben Morones-Ramirez, Universidad Autónoma de Nuevo León, Mexico; Jozsef Soki, University of Szeged, Hungary
Updates
Copyright
© 2019 Rizvanov, Haertlé, Bogomolnaya and Talebi Bezmin Abadi.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Albert A. Rizvanov, rizvanov@gmail.comAmin Talebi Bezmin Abadi, amin.talebi@modares.ac.ir
This article was submitted to Antimicrobials, Resistance and Chemotherapy, a section of the journal Frontiers in Microbiology
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