Russian Journal of Infection and ImmunityRussian Journal of Infection and Immunity2220-76192313-7398SPb RAACI182510.15789/2220-7619-COM-1825Review ArticleConvergence of multiple resistance and hypervirulence in Klebsiella pneumoniaeAgeevetsVladimir A.<p>PhD (Biology), Researcher, Research Department of Medical Microbiology and Molecular Epidemiology</p>ageevets@list.ruhttps://orcid.org/0000-0002-3963-0144AgeevetsI. V.<p>PhD (Medicine), Researcher, Research Department of Medical Microbiology and Molecular Epidemiology</p>partina-irina@yandex.ruhttps://orcid.org/0000-0002-3549-3525SidorenkoS. V.<p>PhD, MD (Medicine), Professor, Head of the Research Department of Medical Microbiology and Molecular Epidemiology</p>sidorserg@gmail.comhttps://orcid.org/0000-0003-3550-7875Paediatric Research and Clinical Centre for Infectious DiseasesPaediatric Research and Clinical Centre for Infectious Diseases,040720221234504601711202128012022Copyright © 2022, Ageevets V.A., Ageevets I.V., Sidorenko S.V.2022<p>Since 2018, <em>Klebsiella pneumoniae</em> isolates have been described in Russia, demonstrating the convergence of hypervirulent properties and multiple antibiotic resistance. The problem of the Klebsiella hypervirulent pathotype has been actualized relatively recently that was progressively described in the 1980s in the Pacific region. These <em>Klebsiella</em> spp. can cause serious community-acquired infections in healthy people, which fundamentally differs from the classic Klebsiella pathotype initially preserving sensitivity to most antibacterial drugs. In 20182020, there were reported detection of hypervirulent <em>K. pneumoniae</em> isolates in the Russian Federation. Like multiple resistance, hypervirulence is associated with the acquiring additional genetic material and formation of genetic lineages that effectively support such acquired determinants. For a long time, it was believed that the convergence of multiple resistance and hypervirulence is unlikely due to a large genetic burden as well as different ecological strategies in same species. The spread of hypervirulent strains, primarily in the Asian region, is associated with the conserved plasmids of the pLVPK group. The conservatism of both the originally discovered virulence plasmids (such as pLVPK and pK2044) and the genetic lineages associated with them (mainly CG23) is probably determined by the absence of a gene cluster responsible for conjugation in these plasmids. The driver of the spread of non-conjugative plasmids with determinants of hypervirulence is clonal spread, not horizontal gene transfer. Nevertheless, after a sufficiently long period of circulation of plasmids bearing markers of hypervirulence (described since 1986) in Klebsiella, a relatively limited number of genetic lineages, there were events of mobilization of the determinants of hypervirulence and, as a consequence, the inclusion in horizontal gene transfer in the population (described cases in 2016 ), which led to a sharp increase in the number of genetic lineages and variants of genetic platforms carrying hypervirulence genes. In Russia, first cases of hv-MDR-Kpn were described in 2018 in Moscow based on analyzing collection of Klebsiella isolated in 20122016. In 2020 and 2021, similar cases were described in St. Petersburg. In case of repeated pessimistic scenario observed over the last decade due to spread of carbapenemases, effectiveness of health care will be more than substantially harmed.</p>Klebsiella sp.hypervirulencemulti-drug resistancehybrid pathotypemobile genetic elementsepidemiologyKlebsiella sp.гипервирулентностьмножественная резистентностьгибридный патотипмобильные генетические элементыэпидемиология[Amako K., Meno Y., Takade A. Fine structures of the capsules of Klebsiella pneumoniae and Escherichia coli K1. J. Bacteriol., 1988, vol. 170, no. 10, pp. 4960–4962. doi: 10.1128/jb.170.10.4960-4962.1988][Arato V., Raso M.M., Gasperini G., Berlanda Scorza F., Micoli F. Prophylaxis and treatment against Klebsiella pneumoniae: current insights on this emerging anti-microbial resistant global threat. Int. J. Mol. Sci., 2021, vol. 22, no. 8. doi: 10.3390/ijms22084042][Bensley E.H. A case of Friedlander’s pneumonia. Can. Med. Assoc. J., 1932, vol. 26, no. 6, pp. 681–684.][Bernhard W., Gbarah A., Sharon N. Lectinophagocytosis of type 1 fimbriated (mannose-specific) Escherichia coli in the mouse peritoneum. J. Leukoc. Biol., 1992, vol. 52, no. 3, pp. 343–348. doi: 10.1002/jlb.52.3.343][Bialek-Davenet S., Criscuolo A., Ailloud F., Passet V., Jones L., Delannoy-Vieillard A.S., Garin B., Le Hello S., Arlet G., Nicolas-Chanoine M.H., Decre D., Brisse S. Genomic definition of hypervirulent and multidrug-resistant Klebsiella pneumoniae clonal groups. Emerg. Infect. Dis., 2014, vol. 20, no. 11, pp. 1812–1820. doi: 10.3201/eid2011.140206][Brisse S., Fevre C., Passet V., Issenhuth-Jeanjean S., Tournebize R., Diancourt L., Grimont P. Virulent clones of Klebsiella pneumoniae: identification and evolutionary scenario based on genomic and phenotypic characterization. PLoS One, 2009, vol. 4, no. 3: e4982. doi: 10.1371/journal.pone.0004982][Brown J.S., Holden D.W. Iron acquisition by Gram-positive bacterial pathogens. Microbes Infect., 2002, vol. 4, no. 11, pp. 1149–1156. doi: 10.1016/s1286-4579(02)01640-4][Chen Y.T., Chang H.Y., Lai Y.C., Pan C.C., Tsai S.F., Peng H.L. Sequencing and analysis of the large virulence plasmid pLVPK of Klebsiella pneumoniae CG43. Gene, 2004, vol. 337, pp. 189–198. doi: 10.1016/j.gene.2004.05.008][Clarke B.R., Ovchinnikova O.G., Kelly S.D., Williamson M.L., Butler J.E., Liu B., Wang L., Gou X., Follador R., Lowary T.L., Whitfield C. Molecular basis for the structural diversity in serogroup O2-antigen polysaccharides in Klebsiella pneumoniae. J. Biol. Chem., 2018, vol. 293, no. 13, pp. 4666–4679. doi: 10.1074/jbc.RA117.000646][Di Martino P., Livrelli V., Sirot D., Joly B., Darfeuille-Michaud A. A new fimbrial antigen harbored by CAZ-5/SHV-4-producing Klebsiella pneumoniae strains involved in nosocomial infections. Infect. Immun., 1996, vol. 64, no. 6, pp. 2266–2273. doi: 10.1128/iai.64.6.2266-2273.1996][Dong N., Sun Q., Huang Y., Shu L., Ye L., Zhang R., Chen S. Evolution of carbapenem-resistant serotype K1 hypervirulent Klebsiella pneumoniae by acquisition of bla VIM-1-bearing plasmid. Antimicrob. Agents Chemother., 2019, vol. 63, no. 9. doi: 10.1128/AAC.01056-19][Feldman M.F., Mayer Bridwell A.E., Scott N.E., Vinogradov E., McKee S.R., Chavez S.M., Twentyman J., Stallings C.L., Rosen D.A., Harding C.M. A promising bioconjugate vaccine against hypervirulent Klebsiella pneumoniae. Proc. Natl Acad. Sci. USA, 2019, vol. 116, no. 37, pp. 18655–18663. doi: 10.1073/pnas.1907833116][Follador R., Heinz E., Wyres K.L., Ellington M.J., Kowarik M., Holt K.E., Thomson N.R. The diversity of Klebsiella pneumoniae surface polysaccharides. Microb Genom., 2016, vol. 2, no. 8: e000073. doi: 10.1099/mgen.0.000073][Fung C.P., Chang F.Y., Lee S.C., Hu B.S., Kuo B.I., Liu C.Y., Ho M., Siu L.K. A global emerging disease of Klebsiella pneumoniae liver abscess: is serotype K1 an important factor for complicated endophthalmitis? Gut, 2002, vol. 50, no. 3, pp. 420–424. doi: 10.1136/gut.50.3.420][Gu D., Dong N., Zheng Z., Lin D., Huang M., Wang L., Chan E.W., Shu L., Yu J., Zhang R., Chen S. A fatal outbreak of ST11 carbapenem-resistant hypervirulent Klebsiella pneumoniae in a Chinese hospital: a molecular epidemiological study. Lancet Infect. Dis., 2018, vol. 18, no. 1, pp. 37–46. doi: 10.1016/S1473-3099(17)30489-9][Guo C., Yang X., Wu Y., Yang H., Han Y., Yang R., Hu L., Cui Y., Zhou D. MLST-based inference of genetic diversity and population structure of clinical Klebsiella pneumoniae, China. Sci. Rep., 2015, vol. 5: 7612. doi: 10.1038/srep07612][Harada S., Aoki K., Ishii Y., Ohno Y., Nakamura A., Komatsu M., Tateda K. Emergence of IMP-producing hypervirulent Klebsiella pneumoniae carrying a pLVPK-like virulence plasmid. Int. J. Antimicrob. Agents, 2019, vol. 53, no. 6, pp. 873–875. doi: 10.1016/j.ijantimicag.2019.05.007][Holmes R.B. Friedländer’s pneumonia. Am. J. Roentgenol. Radium Ther. Nucl. Med., 1956, vol. 75, no. 4, pp. 728–745.][Holt K.E., Wertheim H., Zadoks R.N., Baker S., Whitehouse C.A., Dance D., Jenney A., Connor T.R., Hsu L.Y., Severin J., Brisse S., Cao H., Wilksch J., Gorrie C., Schultz M.B., Edwards D.J., Nguyen K.V., Nguyen T.V., Dao T.T., Mensink M., Minh V.L., Nhu N.T., Schultsz C., Kuntaman K., Newton P.N., Moore C.E., Strugnell R.A., Thomson N.R. Genomic analysis of diversity, population structure, virulence, and antimicrobial resistance in Klebsiella pneumoniae, an urgent threat to public health. Proc. Natl Acad. Sci. USA, 2015, vol. 112, no. 27: E3574-81. doi: 10.1073/pnas.1501049112][Lam M.M.C., Wyres K.L., Duchene S., Wick R.R., Judd L.M., Gan Y.H., Hoh C.H., Archuleta S., Molton J.S., Kalimuddin S., Koh T.H., Passet V., Brisse S., Holt K.E. Population genomics of hypervirulent Klebsiella pneumoniae clonal-group 23 reveals early emergence and rapid global dissemination. Nat. Commun., 2018, vol. 9, no. 1: 2703. doi: 10.1038/s41467-018-05114-7][Lampe W.T. Klebsiella pneumoniae. A review of forty-five and re-evaluation of the incidence and antibiotic sensitivities. Dis. Chest., 1964, vol. 46, pp. 599–606. doi: 10.1378/chest.46.5.599][Lan P., Jiang Y., Zhou J., Yu Y. A global perspective on the convergence of hypervirulence and carbapenem resistance in Klebsiella pneumoniae. J. Glob. Antimicrob. Resist., 2021, vol. 25, pp. 26–34. doi: 10.1016/j.jgar.2021.02.020][Lazareva I., Ageevets V., Sopova J., Lebedeva M., Starkova P., Likholetova D., Gostev V., Moiseenko V., Egorenkov V., Navatskaya A., Mitroshina G., Myasnikova E., Tsvetkova I., Lobzin Y., Sidorenko S. The emergence of hypervirulent blaNDM-1- positive Klebsiella pneumoniae sequence type 395 in an oncology hospital. Infect. Genet. Evol., 2020, vol. 85: 104527. doi: 10.1016/ j.meegid.2020.104527][Lev A.I., Astashkin E.I., Kislichkina A.A., Solovieva E.V., Kombarova T.I., Korobova O.V., Ershova O.N., Alexandrova I.A., Malikov V.E., Bogun A.G., Borzilov A.I., Volozhantsev N.V., Svetoch E.A., Fursova N.K. Comparative analysis of Klebsiella pneumoniae strains isolated in 2012–2016 that differ by antibiotic resistance genes and virulence genes profiles. Pathog. Glob. Health., 2018, vol. 112, no. 3, pp. 142–151. doi: 10.1080/20477724.2018.1460949][Liao C.H., Huang Y.T., Chang C.Y., Hsu H.S., Hsueh P.R. Capsular serotypes and multilocus sequence types of bacteremic Klebsiella pneumoniae isolates associated with different types of infections. Eur. J. Clin. Microbiol. Infect. Dis., 2014, vol. 33, no. 3, pp. 365–369. doi: 10.1007/s10096-013-1964-z][Liu Y., Long D., Xiang T.X., Du F.L., Wei D.D., Wan L.G., Deng Q., Cao X.W., Zhang W. Whole genome assembly and functional portrait of hypervirulent extensively drug-resistant NDM-1 and KPC-2 co-producing Klebsiella pneumoniae of capsular serotype K2 and ST86. J. Antimicrob. Chemother., 2019, vol. 74, no. 5, pp. 1233–1240. doi: 10.1093/jac/dkz023][Liu Y.C., Cheng D.L., Lin C.L. Klebsiella pneumoniae liver abscess associated with septic endophthalmitis. Arch. Intern. Med., 1986, vol. 146, no. 10, pp. 1913–1916.][Luo Y., Wang Y., Ye L., Yang J. Molecular epidemiology and virulence factors of pyogenic liver abscess causing Klebsiella pneumoniae in China. Clin. Microbiol. Infect., 2014, vol. 20, no. 11: O818-24. doi: 10.1111/1469-0691.12664][Moradali M.F., Rehm B.H.A. Bacterial biopolymers: from pathogenesis to advanced materials. Nat. Rev. Microbiol., 2020, vol. 18, no. 4, pp. 195–210. doi: 10.1038/s41579-019-0313-3][Nassif X., Fournier J.M., Arondel J., Sansonetti P.J. Mucoid phenotype of Klebsiella pneumoniae is a plasmid-encoded virulence factor. Infect. Immun., 1989, vol. 57, no. 2, pp. 546–552. doi: 10.1128/iai.57.2.546-552.1989][Nassif X., Honoré N., Vasselon T., Cole S.T., Sansonetti P.J. Positive control of colanic acid synthesis in Escherichia coli by rmpA and rmpB, two virulence-plasmid genes of Klebsiella pneumoniae. Mol. Microbiol., 1989, vol. 3, no. 10, pp. 1349–1359. doi: 10.1111/j.1365-2958.1989.tb00116.x][Nassif X., Sansonetti P.J. Correlation of the virulence of Klebsiella pneumoniae K1 and K2 with the presence of a plasmid encoding aerobactin. Infect. Immun., 1986, vol. 54, no. 3, pp. 603–608. doi: 10.1128/iai.54.3.603-608.1986][Oseasohn R. Friedlander’s pneumonia. Med. Sci., 1962, vol. 11, pp. 1000–1008.][Pan Y.J., Lin T.L., Chen C.T., Chen Y.Y., Hsieh P.F., Hsu C.R., Wu M.C., Wang J.T. Genetic analysis of capsular polysaccharide synthesis gene clusters in 79 capsular types of Klebsiella spp. Sci. Rep., 2015, vol. 5: 15573. doi: 10.1038/srep15573][Posey J.E., Gherardini F.C. Lack of a role for iron in the Lyme disease pathogen. Science, 2000, vol. 288, no. 5471, pp. 1651–1653. doi: 10.1126/science.288.5471.1651][Russo T.A., MacDonald U. The Galleria mellonella infection model does not accurately differentiate between hypervirulent and classical Klebsiella pneumoniae. mSphere, 2020, vol. 5, no. 1: e00850-19. doi: 10.1128/mSphere.00850-19][Russo T.A., Marr C.M. Hypervirulent Klebsiella pneumoniae. Clin. Microbiol. Rev., 2019, vol. 32, no. 3: e00001-19. doi: 10.1128/CMR.00001-19][Russo T.A., Olson R., Fang C.T., Stoesser N., Miller M., MacDonald U., Hutson A., Barker J.H., La Hoz R.M., Johnson J.R. Identification of Biomarkers for Differentiation of Hypervirulent Klebsiella pneumoniae from Classical K. pneumoniae. J. Clin. Microbiol., 2018, vol. 56, no. 9. doi: 10.1128/JCM.00776-18][Russo T.A., Olson R., Macdonald U., Metzger D., Maltese L.M., Drake E.J., Gulick A.M. Aerobactin mediates virulence and accounts for increased siderophore production under iron-limiting conditions by hypervirulent (hypermucoviscous) Klebsiella pneumoniae. Infect. Immun., 2014, vol. 82, no. 6, pp. 2356–2367. doi: 10.1128/IAI.01667-13][Sebghati T.A., Korhonen T.K., Hornick D.B., Clegg S. Characterization of the type 3 fimbrial adhesins of Klebsiella strains. Infect. Immun., 1998, vol. 66, no. 6, pp. 2887–2894. doi: 10.1128/IAI.66.6.2887-2894.1998][Shaidullina E., Shelenkov A., Yanushevich Y., Mikhaylova Y., Shagin D., Alexandrova I., Ershova O., Akimkin V., Kozlov R., Edelstein M. Antimicrobial resistance and genomic characterization of OXA-48- and CTX-M-15-co-producing hypervirulent Klebsiella pneumoniae ST23 recovered from nosocomial outbreak. Antibiotics (Basel)., 2020, vol. 9, no. 12. doi: 10.3390/antibiotics9120862][Sharon N. Bacterial lectins, cell-cell recognition and infectious disease. FEBS Lett., 1987, vol. 217, no. 2, pp. 145–157. doi: 10.1016/0014-5793(87)80654-3][Shelenkov A., Mikhaylova Y., Yanushevich Y., Samoilov A., Petrova L., Fomina V., Gusarov V., Zamyatin M., Shagin D., Akimkin V. Molecular typing, characterization of antimicrobial resistance, virulence profiling and analysis of whole-genome sequence of clinical Klebsiella pneumoniae isolates. Antibiotics (Basel)., 2020, vol. 9, no. 5. doi: 10.3390/antibiotics9050261][Shon A.S., Bajwa R.P., Russo T.A. Hypervirulent (hypermucoviscous) Klebsiella pneumoniae: a new and dangerous breed. Virulence, 2013, vol. 4, no. 2, pp. 107–118. doi: 10.4161/viru.22718][Starkova P., Lazareva I., Avdeeva A., Sulian O., Likholetova D., Ageevets V., Lebedeva M., Gostev V., Sopova J., Sidorenko S. Emergence of hybrid resistance and virulence plasmids harboring new delhi metallo-beta-lactamase in Klebsiella pneumoniae in Russia. Antibiotics (Basel)., 2021, vol. 10, no. 6. doi: 10.3390/antibiotics10060691][Struve C., Bojer M., Krogfelt K.A. Characterization of Klebsiella pneumoniae type 1 fimbriae by detection of phase variation during colonization and infection and impact on virulence. Infect. Immun., 2008, vol. 76, no. 9, pp. 4055–4065. doi: 10.1128/IAI.00494-08][Struve C., Roe C.C., Stegger M., Stahlhut S.G., Hansen D.S., Engelthaler D.M., Andersen P.S., Driebe E.M., Keim P., Krogfelt K.A. Mapping the evolution of hypervirulent Klebsiella pneumoniae. mBio, 2015, vol. 6, no. 4: e00630. doi: 10.1128/mBio.00630-15][Tang H.L., Chiang M.K., Liou W.J., Chen Y.T., Peng H.L., Chiou C.S., Liu K.S., Lu M.C., Tung K.C., Lai Y.C. Correlation between Klebsiella pneumoniae carrying pLVPK-derived loci and abscess formation. Eur. J. Clin. Microbiol. Infect. Dis., 2010, vol. 29, no. 6, pp. 689–698. doi: 10.1007/s10096-010-0915-1][Tang M., Kong X., Hao J., Liu J. Epidemiological characteristics and formation mechanisms of multidrug-resistant hypervirulent Klebsiella pneumoniae. Front. Microbiol., 2020, vol. 11: 581543. doi: 10.3389/fmicb.2020.581543][Turton J., Davies F., Perry C., Payne Z., Pike R. Hybrid resistance and virulence plasmids in “high-risk” clones of Klebsiella pneumoniae, including those carrying blaNDM-5. Microorganisms, 2019, vol. 7, no. 9. doi: 10.3390/microorganisms7090326][Turton J.F., Payne Z., Coward A., Hopkins K.L., Turton J.A., Doumith M., Woodford N. Virulence genes in isolates of Klebsiella pneumoniae from the UK during 2016, including among carbapenemase gene-positive hypervirulent K1-ST23 and “non-hypervirulent” types ST147, ST15 and ST383. J. Med. Microbiol., 2018, vol. 67, no. 1, pp. 118–128. doi: 10.1099/jmm.0.000653][Walker K.A., Miller V.L. The intersection of capsule gene expression, hypermucoviscosity and hypervirulence in Klebsiella pneumoniae. Curr. Opin. Microbiol., 2020, vol. 54, pp. 95–102. doi: 10.1016/j.mib.2020.01.006][Wu C.C., Huang Y.J., Fung C.P., Peng H.L. Regulation of the Klebsiella pneumoniae Kpc fimbriae by the site-specific recombinase KpcI. Microbiology (Reading), 2010, vol. 156, pt. 7, pp. 1983–1992. doi: 10.1099/mic.0.038158-0][Wu H., Li D., Zhou H., Sun Y., Guo L., Shen D. Bacteremia and other body site infection caused by hypervirulent and classic Klebsiella pneumoniae. Microb. Pathog., 2017, vol. 104, pp. 254–262. doi: 10.1016/j.micpath.2017.01.049][Wyres K.L., Wick R.R., Gorrie C., Jenney A., Follador R., Thomson N.R., Holt K.E. Identification of Klebsiella capsule synthesis loci from whole genome data. Microbial Genomics, 2016, vol. 2, no. 12. doi: 10.1099/mgen.0.000102][Yeh K.M., Kurup A., Siu L.K., Koh Y.L., Fung C.P., Lin J.C., Chen T.L., Chang F.Y., Koh T.H. Capsular serotype K1 or K2, rather than magA and rmpA, is a major virulence determinant for Klebsiella pneumoniae liver abscess in Singapore and Taiwan. J. Clin. Microbiol., 2007, vol. 45, no. 2, pp. 466–471. doi: 10.1128/JCM.01150-06][Yu W.L., Ko W.C., Cheng K.C., Lee C.C., Lai C.C., Chuang Y.C. Comparison of prevalence of virulence factors for Klebsiella pneumoniae liver abscesses between isolates with capsular K1/K2 and non-K1/K2 serotypes. Diagn. Microbiol. Infect. Dis., 2008, vol. 62, no. 1, pp. 1–6. doi: 10.1016/j.diagmicrobio.2008.04.007][Zhang R., Liu L., Zhou H., Chan E.W., Li J., Fang Y., Li Y., Liao K., Chen S. Nationwide surveillance of clinical carbapenem-resistant Enterobacteriaceae (CRE) strains in China. eBioMedicine, 2017, vol. 19, pp. 98–106. doi: 10.1016/j.ebiom.2017.04.032]