Abstract
Klebsiella pneumoniae is responsible for a wide range of infections, including urinary tract infections, pneumonia, bacteremia, and liver abscesses. In addition to susceptible clinical isolates involved in nosocomial infections, multidrug-resistant (MDR) and hypervirulent (hvKP) strains have evolved separately in distinct clonal groups. The rapid geographic spread of these isolates is of particular concern. However, we still know little about the virulence of K. pneumoniae except for hvKP, whose secrets are beginning to be revealed. The treatment of K. pneumoniae infections is threatened by the emergence of antimicrobial resistance. The dissemination of resistance is associated with genetic mobile elements, such as plasmids that may also carry virulence determinants. A proficient pathogen should be virulent, resistant to antibiotics, and epidemic. However, the interplay between resistance and virulence is poorly understood. Here, we review current knowledge on the topic.
Similar content being viewed by others
References
Podschun R, Ullmann U (1998) Klebsiella spp. as nosocomial pathogens: epidemiology, taxonomy, typing methods, and pathogenicity factors. Clin Microbiol Rev 11:589–603
Chang FY, Chou MY (1995) Comparison of pyogenic liver abscesses caused by Klebsiella pneumoniae and non-K. pneumoniae pathogens. J Formos Med Assoc 94:232–237, Taiwan Yi Zhi
Shon AS, Bajwa RPS, Russo TA (2013) Hypervirulent (hypermucoviscous) Klebsiella pneumoniae: a new and dangerous breed. Virulence 4(2):107–118. doi:10.4161/viru.22718
Luo Y, Wang Y, Ye L, Yang J (2014) Molecular epidemiology and virulence factors of pyogenic liver abscess causing Klebsiella pneumoniae in China. Clin Microbiol Infect 20:O818–O824. doi:10.1111/1469-0691.12664
Bialek-Davenet S, Criscuolo A, Ailloud F, Passet V, Jones L, Delannoy-Vieillard A-S et al (2014) Genomic definition of hypervirulent and multidrug-resistant Klebsiella pneumoniae clonal groups. Emerg Infect Dis 20:1812–1820. doi:10.3201/eid2011.140206
Li B, Yi Y, Wang Q, Woo PCY, Tan L, Jing H et al (2012) Analysis of drug resistance determinants in Klebsiella pneumoniae isolates from a tertiary-care hospital in Beijing, China. PLoS One 7:e42280. doi:10.1371/journal.pone.0042280
Boucher HW, Talbot GH, Bradley JS, Edwards JE, Gilbert D, Rice LB et al (2009) Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis Off 48(1):1–12. doi:10.1086/595011
Yao B, Xiao X, Wang F, Zhou L, Zhang X, Zhang J (2015) Clinical and molecular characteristics of multi-clone carbapenem-resistant hypervirulent (hypermucoviscous) Klebsiella pneumoniae isolates in a tertiary hospital in Beijing, China. Int J Infect Dis 37:107–112. doi:10.1016/j.ijid.2015.06.023
Paterson DL, Bonomo RA (2005) Extended-spectrum beta-lactamases: a clinical update. Clin Microbiol Rev 18:657–686. doi:10.1128/CMR.18.4.657-686.2005
Munoz-Price LS, Poirel L, Bonomo RA, Schwaber MJ, Daikos GL, Cormican M et al (2013) Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases. Lancet Infect Dis 13:785–796. doi:10.1016/S1473-3099(13)70190-7
Chen Y-T, Chang H-Y, Lai Y-C, Pan C-C, Tsai S-F, Peng H-L (2004) Sequencing and analysis of the large virulence plasmid pLVPK of Klebsiella pneumoniae CG43. Gene 337:189–198. doi:10.1016/j.gene.2004.05.008
Lin T-L, Lee C-Z, Hsieh P-F, Tsai S-F, Wang J-T (2008) Characterization of integrative and conjugative element ICEKp1-associated genomic heterogeneity in a Klebsiella pneumoniae strain isolated from a primary liver abscess. J Bacteriol 190:515–526. doi:10.1128/JB.01219-07
Chou H-C, Lee C-Z, Ma L-C, Fang C-T, Chang S-C, Wang J-T (2004) Isolation of a chromosomal region of Klebsiella pneumoniae associated with allantoin metabolism and liver infection. Infect Immun 72:3783–3792. doi:10.1128/IAI.72.7.3783-3792.2004
Holt KE, Wertheim H, Zadoks RN, Baker S, Whitehouse CA, Dance D et al (2015) Genomic analysis of diversity, population structure, virulence, and antimicrobial resistance in Klebsiella pneumoniae, an urgent threat to public health. Proc Natl Acad Sci U S A 112(27):E3574–E3581. doi:10.1073/pnas.1501049112
Da Silva GJ, Mendonça N (2012) Association between antimicrobial resistance and virulence in Escherichia coli. Virulence 3:18–28. doi:10.4161/viru.3.1.18382
Vogwill T, MacLean RC (2015) The genetic basis of the fitness costs of antimicrobial resistance: a meta-analysis approach. Evol Appl 8:284–295. doi:10.1111/eva.12202
Ramirez MS, Traglia GM, Lin DL, Tran T, Tolmasky ME (2014) Plasmid-mediated antibiotic resistance and virulence in gram-negatives: the Klebsiella pneumoniae paradigm. Microbiol Spectr 2:1–15. doi:10.1128/microbiolspec.PLAS-0016-2013
Sirot D, Sirot J, Labia R, Morand A, Courvalin P, Darfeuille-Michaud A et al (1987) Transferable resistance to third-generation cephalosporins in clinical isolates of Klebsiella pneumoniae: identification of CTX-1, a novel beta-lactamase. J Antimicrob Chemother 20:323–334
Calbo E, Garau J (2015) The changing epidemiology of hospital outbreaks due to ESBL-producing Klebsiella pneumoniae: the CTX-M-15 type consolidation. Future Microbiol 10:1063–1075. doi:10.2217/fmb.15.22
Di Martino P, Bertin Y, Girardeau JP, Livrelli V, Joly B, Darfeuille-Michaud A (1995) Molecular characterization and adhesive properties of CF29K, an adhesin of Klebsiella pneumoniae strains involved in nosocomial infections. Infect Immun 63:4336–4344
Darfeuille-Michaud A, Jallat C, Aubel D, Sirot D, Rich C, Sirot J et al (1992) R-plasmid-encoded adhesive factor in Klebsiella pneumoniae strains responsible for human nosocomial infections. Infect Immun 60:44–55
Vernet V, Madoulet C, Chippaux C, Philippon A (1992) Incidence of two virulence factors (aerobactin and mucoid phenotype) among 190 clinical isolates of Klebsiella pneumoniae producing extended-spectrum beta-lactamase. FEMS Microbiol Lett 75(1):1–5
Brisse S, Fevre C, Passet V, Issenhuth-Jeanjean S, Tournebize R, Diancourt L et al (2009) Virulent clones of Klebsiella pneumoniae: identification and evolutionary scenario based on genomic and phenotypic characterization. PLoS One 4:e4982. doi:10.1371/journal.pone.0004982
Shin J, Ko KS (2014) Comparative study of genotype and virulence in CTX-M-producing and non-extended-spectrum-β-lactamase-producing Klebsiella pneumoniae isolates. Antimicrob Agents Chemother 58:2463–2467. doi:10.1128/AAC.02499-13
Struve C, Roe CC, Stegger M, Stahlhut SG, Hansen DS, Engelthaler DM et al (2015) Mapping the evolution of hypervirulent Klebsiella pneumoniae. MBio 6:e00630. doi:10.1128/mBio.00630-15
Di Martino P, Livrelli V, Sirot D, Joly B, Darfeuille-Michaud A (1996) A new fimbrial antigen harbored by CAZ-5/SHV-4-producing Klebsiella pneumoniae strains involved in nosocomial infections. Infect Immun 64:2266–2273
Sahly H, Navon-Venezia S, Roesler L, Hay A, Carmeli Y, Podschun R et al (2008) Extended-spectrum beta-lactamase production is associated with an increase in cell invasion and expression of fimbrial adhesins in Klebsiella pneumoniae. Antimicrob Agents Chemother 52:3029–3034. doi:10.1128/AAC.00010-08
Livrelli V, De Champs C, Di Martino P, Darfeuille-Michaud A, Forestier C, Joly B (1996) Adhesive properties and antibiotic resistance of Klebsiella, Enterobacter, and Serratia clinical isolates involved in nosocomial infections. J Clin Microbiol 34:1963–1969
Sahly H, Aucken H, Benedí VJ, Forestier C, Fussing V, Hansen DS et al (2004) Increased serum resistance in Klebsiella pneumoniae strains producing extended-spectrum β-lactamases. Antimicrob Agents Chemother 48(9):3477–3482. doi:10.1128/AAC.48.9.3477-3482.2004
Robin F, Hennequin C, Gniadkowski M, Beyrouthy R, Empel J, Gibold L et al (2012) Virulence factors and TEM-type β-lactamases produced by two isolates of an epidemic Klebsiella pneumoniae strain. Antimicrob Agents Chemother 56:1101–1104. doi:10.1128/AAC.05079-11
El Fertas-Aissani R, Messai Y, Alouache S, Bakour R (2013) Virulence profiles and antibiotic susceptibility patterns of Klebsiella pneumoniae strains isolated from different clinical specimens. Pathol Biol (Paris) 61:209–216. doi:10.1016/j.patbio.2012.10.004
Hennequin C, Forestier C (2007) Influence of capsule and extended-spectrum beta-lactamases encoding plasmids upon Klebsiella pneumoniae adhesion. Res Microbiol 158:339–347. doi:10.1016/j.resmic.2007.02.005
Hennequin C, Aumeran C, Robin F, Traore O, Forestier C (2012) Antibiotic resistance and plasmid transfer capacity in biofilm formed with a CTX-M-15-producing Klebsiella pneumoniae isolate. J Antimicrob Chemother 67:2123–2130. doi:10.1093/jac/dks169
Wand ME, Baker KS, Benthall G, McGregor H, McCowen JWI, Deheer-Graham A et al (2015) Characterization of pre-antibiotic era Klebsiella pneumoniae isolates with respect to antibiotic/disinfectant susceptibility and virulence in Galleria mellonella. Antimicrob Agents Chemother 59:3966–3972. doi:10.1128/AAC.05009-14
Sandegren L, Linkevicius M, Lytsy B, Melhus Å, Andersson DI (2012) Transfer of an Escherichia coli ST131 multiresistance cassette has created a Klebsiella pneumoniae-specific plasmid associated with a major nosocomial outbreak. J Antimicrob Chemother 67:74–83. doi:10.1093/jac/dkr405
Shin J, Soo KK (2014) Single origin of three plasmids bearing blaCTX-M-15 from different Klebsiella pneumoniae clones. J Antimicrob Chemother 69:969–972. doi:10.1093/jac/dkt464
Yu W-L, Lee M-F, Tang H-J, Chang M-C, Chuang Y-C (2015) Low prevalence of rmpA and high tendency of rmpA mutation correspond to low virulence of extended spectrum β-lactamase-producing Klebsiella pneumoniae isolates. Virulence 6:162–172. doi:10.1080/21505594.2015.1016703
Philippon A, Arlet G, Jacoby GA (2002) Plasmid-determined AmpC-type beta-lactamases. Antimicrob Agents Chemother 46:1–11
Barnaud G, Arlet G, Verdet C, Gaillot O, Lagrange PH, Philippon A (1998) Salmonella enteritidis: AmpC plasmid-mediated inducible beta-lactamase (DHA-1) with an ampR gene from Morganella morganii. Antimicrob Agents Chemother 42:2352–2358
Compain F, Decré D, Fulgencio J-P, Berraho S, Arlet G, Verdet C (2014) Molecular characterization of DHA-1-producing Klebsiella pneumoniae isolates collected during a 4-year period in an intensive care unit. Diagn Microbiol Infect Dis 80:159–161. doi:10.1016/j.diagmicrobio.2014.06.009
Hennequin C, Robin F, Cabrolier N, Bonnet R, Forestier C (2012) Characterization of a DHA-1-producing Klebsiella pneumoniae strain involved in an outbreak and role of the AmpR regulator in virulence. Antimicrob Agents Chemother 56:288–294. doi:10.1128/AAC.00164-11
Yigit H, Queenan AM, Anderson GJ, Domenech-Sanchez A, Biddle JW, Steward CD et al (2001) Novel carbapenem-hydrolyzing beta-lactamase, KPC-1, from a carbapenem-resistant strain of Klebsiella pneumoniae. Antimicrob Agents Chemother 45:1151–1161. doi:10.1128/AAC.45.4.1151-1161.2001
Lavigne J-P, Cuzon G, Combescure C, Bourg G, Sotto A, Nordmann P (2013) Virulence of Klebsiella pneumoniae isolates harboring bla KPC-2 carbapenemase gene in a Caenorhabditis elegans model. PLoS One 8:e67847. doi:10.1371/journal.pone.0067847
Hammerum AM, Toleman MA, Hansen F, Kristensen B, Lester CH, Walsh TR et al (2010) Global spread of New Delhi metallo-β-lactamase 1. Lancet Infect Dis 10:829–830. doi:10.1016/S1473-3099(10)70276-0
Poirel L, Héritier C, Tolün V, Nordmann P (2004) Emergence of oxacillinase-mediated resistance to imipenem in Klebsiella pneumoniae. Antimicrob Agents Chemother 48:15–22
Voulgari E, Zarkotou O, Ranellou K, Karageorgopoulos DE, Vrioni G, Mamali V et al (2013) Outbreak of OXA-48 carbapenemase-producing Klebsiella pneumoniae in Greece involving an ST11 clone. J Antimicrob Chemother 68:84–88. doi:10.1093/jac/dks356
Siu LK, Lin J-C, Gomez E, Eng R, Chiang T (2012) Virulence and plasmid transferability of KPC Klebsiella pneumoniae at the Veterans Affairs Healthcare System of New Jersey. Microb Drug Resist 18:380–384. doi:10.1089/mdr.2011.0241
De Rosa FG, Corcione S, Cavallo R, Di Perri G, Bassetti M (2015) Critical issues for Klebsiella pneumoniae KPC-carbapenemase producing K. pneumoniae infections: a critical agenda. Future Microbiol 10:283–294. doi:10.2217/fmb.14.121
McLaughlin MM, Advincula MR, Malczynski M, Barajas G, Qi C, Scheetz MH (2014) Quantifying the clinical virulence of Klebsiella pneumoniae producing carbapenemase Klebsiella pneumoniae with a Galleria mellonella model and a pilot study to translate to patient outcomes. BMC Infect Dis 14:31. doi:10.1186/1471-2334-14-31
Beyrouthy R, Robin F, Dabboussi F, Mallat H, Hamzé M, Bonnet R (2014) Carbapenemase and virulence factors of Enterobacteriaceae in North Lebanon between 2008 and 2012: evolution via endemic spread of OXA-48. J Antimicrob Chemother 69:2699–2705. doi:10.1093/jac/dku181
Fuursted K, Schøler L, Hansen F, Dam K, Bojer MS, Hammerum AM et al (2012) Virulence of a Klebsiella pneumoniae strain carrying the New Delhi metallo-beta-lactamase-1 (NDM-1). Microbes Infect 14:155–158. doi:10.1016/j.micinf.2011.08.015
Chen J-H, Siu LK, Fung C-P, Lin J-C, Yeh K-M, Chen T-L et al (2010) Contribution of outer membrane protein K36 to antimicrobial resistance and virulence in Klebsiella pneumoniae. J Antimicrob Chemother 65:986–990. doi:10.1093/jac/dkq056
Kurupati P, Teh BK, Kumarasinghe G, Poh CL (2006) Identification of vaccine candidate antigens of an ESBL producing Klebsiella pneumoniae clinical strain by immunoproteome analysis. Proteomics 6:836–844. doi:10.1002/pmic.200500214
Tsai Y-K, Fung C-P, Lin J-C, Chen J-H, Chang F-Y, Chen T-L et al (2011) Klebsiella pneumoniae outer membrane porins OmpK35 and OmpK36 play roles in both antimicrobial resistance and virulence. Antimicrob Agents Chemother 55:1485–1493. doi:10.1128/AAC.01275-10
Bialek S, Lavigne J-P, Chevalier J, Marcon E, Leflon-Guibout V, Davin A et al (2010) Membrane efflux and influx modulate both multidrug resistance and virulence of Klebsiella pneumoniae in a Caenorhabditis elegans model. Antimicrob Agents Chemother 54:4373–4378. doi:10.1128/AAC.01607-09
March C, Cano V, Moranta D, Llobet E, Pérez-Gutiérrez C, Tomás JM et al (2013) Role of bacterial surface structures on the interaction of Klebsiella pneumoniae with phagocytes. PLoS One 8:e56847. doi:10.1371/journal.pone.0056847
De Champs C, Rich C, Chandezon P, Chanal C, Sirot D, Forestier C (2004) Factors associated with antimicrobial resistance among clinical isolates of Klebsiella pneumoniae: 1-year survey in a French university hospital. Eur J Clin Microbiol Infect Dis 23:456–462. doi:10.1007/s10096-004-1144-2
Piddock LJV (2006) Multidrug-resistance efflux pumps—not just for resistance. Nat Rev Microbiol 4:629–636. doi:10.1038/nrmicro1464
Padilla E, Llobet E, Doménech-Sánchez A, Martínez-Martínez L, Bengoechea JA, Albertí S (2010) Klebsiella pneumoniae AcrAB efflux pump contributes to antimicrobial resistance and virulence. Antimicrob Agents Chemother 54:177–183. doi:10.1128/AAC.00715-09
Veleba M, Higgins PG, Gonzalez G, Seifert H, Schneiders T (2012) Characterization of RarA, a novel AraC family multidrug resistance regulator in Klebsiella pneumoniae. Antimicrob Agents Chemother 56:4450–4458. doi:10.1128/AAC.00456-12
Bialek-Davenet S, Lavigne J-P, Guyot K, Mayer N, Tournebize R, Brisse S et al (2015) Differential contribution of AcrAB and OqxAB efflux pumps to multidrug resistance and virulence in Klebsiella pneumoniae. J Antimicrob Chemother 70:81–88. doi:10.1093/jac/dku340
Ogawa W, Onishi M, Ni R, Tsuchiya T, Kuroda T (2012) Functional study of the novel multidrug efflux pump KexD from Klebsiella pneumoniae. Gene 498(2):177–182. doi:10.1016/j.gene.2012.02.008
Coudeyras S, Nakusi L, Charbonnel N, Forestier C (2008) A tripartite efflux pump involved in gastrointestinal colonization by Klebsiella pneumoniae confers a tolerance response to inorganic acid. Infect Immun 76:4633–4641. doi:10.1128/IAI.00356-08
Ogawa W, Minato Y, Dodan H, Onishi M, Tsuchiya T, Kuroda T (2015) Characterization of MATE-type multidrug efflux pumps from Klebsiella pneumoniae MGH78578. PLoS One 10:e0121619. doi:10.1371/journal.pone.0121619
Mazzariol A, Zuliani J, Cornaglia G, Rossolini GM, Fontana R (2002) AcrAB efflux system: expression and contribution to fluoroquinolone resistance in Klebsiella spp. Antimicrob Agents Chemother 46:3984–3986
Liao C-H, Hsueh P-R, Jacoby GA, Hooper DC (2013) Risk factors and clinical characteristics of patients with qnr-positive Klebsiella pneumoniae bacteraemia. J Antimicrob Chemother 68:2907–2914. doi:10.1093/jac/dkt295
Tóth A, Kocsis B, Damjanova I, Kristóf K, Jánvári L, Pászti J et al (2014) Fitness cost associated with resistance to fluoroquinolones is diverse across clones of Klebsiella pneumoniae and may select for CTX-M-15 type extended-spectrum β-lactamase. Eur J Clin Microbiol Infect Dis 33:837–843. doi:10.1007/s10096-013-2022-6
Ah Y-M, Kim A-J, Lee J-Y (2014) Colistin resistance in Klebsiella pneumoniae. Int J Antimicrob Agents 44:8–15. doi:10.1016/j.ijantimicag.2014.02.016
Cannatelli A, D’Andrea MM, Giani T, Di Pilato V, Arena F, Ambretti S et al (2013) In vivo emergence of colistin resistance in Klebsiella pneumoniae producing KPC-type carbapenemases mediated by insertional inactivation of the PhoQ/PhoP mgrB regulator. Antimicrob Agents Chemother 57:5521–5526. doi:10.1128/AAC.01480-13
Wright MS, Suzuki Y, Jones MB, Marshall SH, Rudin SD, van Duin D et al (2015) Genomic and transcriptomic analyses of colistin-resistant clinical isolates of Klebsiella pneumoniae reveal multiple pathways of resistance. Antimicrob Agents Chemother 59:536–543. doi:10.1128/AAC.04037-14
Choi M-J, Ko KS (2015) Loss of hypermucoviscosity and increased fitness cost in colistin-resistant Klebsiella pneumoniae sequence type 23 strains. Antimicrob Agents Chemother 59:6763–6773. doi:10.1128/AAC.00952-15
Liu Y-Y, Wang Y, Walsh TR, Yi L-X, Zhang R, Spencer J et al (2015) Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis. pii: S1473-3099(15)00424-7. doi:10.1016/S1473-3099(15)00424-7
Ramos PIP, Picão RC, de Almeida LGP, Lima NCB, Girardello R, Vivan ACP et al (2014) Comparative analysis of the complete genome of KPC-2-producing Klebsiella pneumoniae Kp13 reveals remarkable genome plasticity and a wide repertoire of virulence and resistance mechanisms. BMC Genomics 15:54. doi:10.1186/1471-2164-15-54
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Hennequin, C., Robin, F. Correlation between antimicrobial resistance and virulence in Klebsiella pneumoniae . Eur J Clin Microbiol Infect Dis 35, 333–341 (2016). https://doi.org/10.1007/s10096-015-2559-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10096-015-2559-7