Impact of Carbapenem Heteroresistance Among Multidrug-Resistant ESBL/AmpC-Producing Klebsiella pneumoniae Clinical Isolates on Antibiotic Treatment in Experimentally Infected Mice
Open accessAbstract
Purpose: Antibiotic resistance is a growing health crisis that is further complicated by treatment failures caused by bacteria that exhibit heterogeneous susceptibility to antibiotics. The aim of this study was to describe imipenem (IPM)-heteroresistant strains among multidrug-resistant (MDR) ESBL/AmpC-producing Klebsiella pneumoniae clinical isolates, investigate their molecular phenotypic characteristics, and elucidate the outcome of antibiotic treatment in mice infected with the heteroresistant isolates. Materials and Methods: Antimicrobial susceptibility of K. pneumoniae isolates was determined by the disk diffusion and E-test methods. Heteroresistance to IPM was confirmed by population analysis profile (PAP) assays. PCR and sequencing were employed to detect MDR determinants. Molecular differences between the susceptible and resistant subpopulations were evaluated by sequencing and quantitative real-time reverse transcription PCR (qRT-PCR) analysis. The effect of the carbapenem-heteroresistant strains on antibiotic treatment was assessed using a mouse model of peritonitis with heteroresistant K. pneumoniae and subsequent treatment with IPM. Results: In total, 37 MDR ESBL/AmpC-producing clinical isolates of K. pneumoniae were identified between September 2018 and December 2019. These strains were notably resistant to conventional antimicrobials other than carbapenems. Among the isolates, three strains exhibited heteroresistance to IPM and carried several ESBL and/or AmpC genes. Mice infected with a lethal dose of any of the three heteroresistant isolates were unable to survive in the presence of IPM treatment, as the percentage of the IPM-resistant subpopulation of each strain was increased in the peritoneum of these mice at 24 h after infection. The resistant subpopulation of the strains presented pulsed-field gel electrophoresis (PFGE) profiles that were identical to those of the susceptible subpopulation, but ompK36 porin showed a reduction in gene expression (0.09- to 0.50-fold) in the resistant subpopulation. Conclusion: Carbapenem-heteroresistant strains were present among the MDR K. pneumoniae isolates producing ESBL/AmpC β-lactamases, and these heteroresistant strains failed IPM therapy in experimentally infected mice. Keywords: Enterobacteriaceae , imipenem, heterogeneous susceptibility, treatment failure, OmpK porin, in vivo
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Cites
Magiorakos, A.-P., Srinivasan, A., Carey, R. B., Carmeli, Y., Falagas, M. E., Giske, C. G., Harbarth, S., Hindler, J. F., Kahlmeter, G., Olsson-Liljequist, B., et al. (2012) · Clinical Microbiology and Infection · doi:10.1111/j.1469-0691.2011.03570.x · Cited by 14,449 · see citing works
Centers for Disease Control and Prevention
Branum, A. (2007) · Sage eBooks · doi:10.4135/9781412952644.n74 · Cited by 6,434 · see citing works
Carbapenemases: the Versatile β-Lactamases
Queenan, A. M., & Bush, K. (2007) · Clinical Microbiology Reviews · doi:10.1128/cmr.00001-07 · Cited by 2,504 · see citing works
The real threat of Klebsiella pneumoniae carbapenemase-producing bacteria
Nordmann, P., Cuzon, G., & Naas, T. (2009) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(09)70054-4 · Cited by 1,583 · see citing works
Detection of Plasmid-Mediated AmpC β-Lactamase Genes in Clinical Isolates by Using Multiplex PCR
Pérez-Pérez, F. J., & Hanson, N. D. (2002) · Journal of Clinical Microbiology · doi:10.1128/jcm.40.6.2153-2162.2002 · Cited by 1,516 · see citing works
Hypervirulent (hypermucoviscous) Klebsiella pneumoniae
Shon, A. S. Y., Bajwa, R. P. S., & Russo, T. A. (2013) · Virulence · doi:10.4161/viru.22718 · Cited by 1,175 · see citing works
Tackling antibiotic resistance
Bush, K., Courvalin, P. M., Dantas, G. A., DAVIES, J. E., Eisenstein, B. I., Huovinen, P., Jacoby, G. A., Kishony, R., Kreiswirth, B. N., Kutter, E. M., et al. (2011) · Nature Reviews Microbiology · doi:10.1038/nrmicro2693 · Cited by 1,082 · see citing works
Grundmann, H., Glasner, C., Albiger, B., Aanensen, D. M., Tomlinson, C. T., Andrašević, A. T., Cantón, R., Carmeli, Y., Friedrich, A. W., Giske, C. G., et al. (2016) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(16)30257-2 · Cited by 669 · see citing works
Gorrie, C. L., Mirčeta, M., Wick, R. R., Edwards, D., Thomson, N. R., Strugnell, R. A., Pratt, N. F., Garlick, J. S., Watson, K., Pilcher, D. V., et al. (2017) · Clinical Infectious Diseases · doi:10.1093/cid/cix270 · Cited by 581 · see citing works
Mechanisms and clinical relevance of bacterial heteroresistance
Andersson, D. I., Nicoloff, H., & Hjort, K. (2019) · Nature Reviews Microbiology · doi:10.1038/s41579-019-0218-1 · Cited by 513 · see citing works
Antimicrobial heteroresistance: An emerging field in need of clarity
El-Halfawy, O. M., & Valvano, M. A. (2015) · Clinical Microbiology Reviews · doi:10.1128/cmr.00058-14 · Cited by 489 · see citing works
Nicoloff, H., Hjort, K., Levin, B. R., & Andersson, D. I. (2019) · Nature Microbiology · doi:10.1038/s41564-018-0342-0 · Cited by 406 · see citing works
Present and Future of Carbapenem-resistant Enterobacteriaceae (CRE) Infections
Suay‐García, B., & Pérez‐Gracia, M. T. (2019) · Antibiotics · doi:10.3390/antibiotics8030122 · Cited by 344 · see citing works
Prevalence of Plasmid-Mediated Quinolone Resistance Determinants over a 9-Year Period
Kim, H. B., Park, C. H., Kim, C.-J., et al. (2008) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01051-08 · Cited by 339 · see citing works
Karaiskos, I., & Giamarellou, H. (2014) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.2014.914172 · Cited by 325 · see citing works
NDM-1 — A Cause for Worldwide Concern
Moellering, R. C. (2010) · New England Journal of Medicine · doi:10.1056/nejmp1011715 · Cited by 313 · see citing works
Turton, J. F., Perry, C., Elgohari, S., et al. (2010) · Journal of Medical Microbiology · doi:10.1099/jmm.0.015198-0 · Cited by 305 · see citing works
Compain, F., Babosan, A., Brisse, S., et al. (2014) · Journal of Clinical Microbiology · doi:10.1128/jcm.02316-14 · Cited by 281 · see citing works
Antibiotic failure mediated by a resistant subpopulation in Enterobacter cloacae
Band, V. I., Crispell, E. K., Napier, B. A., Herrera, C. M., Tharp, G. K., Vavikolanu, K., Pohl, J., Read, T. D., Bosinger, S. E., Trent, M. S., et al. (2016) · Nature Microbiology · doi:10.1038/nmicrobiol.2016.53 · Cited by 248 · see citing works
Heteroresistance: A cause of unexplained antibiotic treatment failure?
Band, V. I., & Weiss, D. S. (2019) · PLoS Pathogens · doi:10.1371/journal.ppat.1007726 · Cited by 212 · see citing works
OmpK36-mediated Carbapenem resistance attenuates ST258 Klebsiella pneumoniae in vivo
Wong, J. L. C., Romanò, M., Kerry, L. E., Kwong, H.-S., Low, W. W., Brett, S. J., Clements, A., Beis, K., & Frankel, G. M. (2019) · Nature Communications · doi:10.1038/s41467-019-11756-y · Cited by 187 · see citing works
Hamzaoui, Z., Ocampo-Sosa, A. A., Martinez, M. F., Landolsi, S., Ferjani, S., Maamar, E., Saïdani, M., Slim, A. F., Martı́nez-Martı́nez, L., & Boubaker, I. B.-B. (2018) · International Journal of Antimicrobial Agents · doi:10.1016/j.ijantimicag.2018.03.020 · Cited by 153 · see citing works
Moore, M. R., Perdreau‐Remington, F., & Chambers, H. F. “. (2003) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.47.4.1262-1266.2003 · Cited by 149 · see citing works
Band, V. I., Satola, S. W., Burd, E. M., Farley, M. M., Jacob, J. T., & Weiss, D. S. (2018) · mBio · doi:10.1128/mbio.02448-17 · Cited by 135 · see citing works
Contribution of OmpK36 to carbapenem susceptibility in KPC-producing Klebsiella pneumoniae
Landman, D., Bratu, S., & Quale, J. M. (2009) · Journal of Medical Microbiology · doi:10.1099/jmm.0.012575-0 · Cited by 130 · see citing works
Klebsiella pneumoniae Bloodstream Infection
Girometti, N., Lewis, R. E., Giannella, M., Ambretti, S., Bartoletti, M., Tedeschi, S., Tumietto, F., Cristini, F., Trapani, F., Gaibani, P., et al. (2014) · Medicine · doi:10.1097/md.0000000000000111 · Cited by 128 · see citing works
Nikaido, H. (1983) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/0076-6879(83)97122-7 · Cited by 111 · see citing works
Antimicrobial Susceptibility Testing: A Primer for Clinicians
Kuper, K. M., Boles, D. M., Mohr, J., & Wanger, A. R. (2009) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1592/phco.29.11.1326 · Cited by 77 · see citing works
Tian, L., Zhang, Z., & Sun, Z. (2019) · Antimicrobial Resistance and Infection Control · doi:10.1186/s13756-019-0545-z · Cited by 77 · see citing works
Pournaras, S., Kristo, I., Vrioni, G., et al. (2010) · Journal of Clinical Microbiology · doi:10.1128/jcm.02134-09 · Cited by 76 · see citing works
Martı́nez-Martı́nez, L., Pascual, Á., Conejo, M. C., Garcı́a, I., Joyanes, P., Doménech‐Sánchez, A., & Benedi, V. J. (2002) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.46.12.3926-3932.2002 · Cited by 68 · see citing works
Netikul, T., & Kiratisin, P. (2015) · PLoS ONE · doi:10.1371/journal.pone.0139116 · Cited by 68 · see citing works
Tato, M., Morosini, M. I., García, L. M., et al. (2010) · Journal of Clinical Microbiology · doi:10.1128/jcm.01130-10 · Cited by 66 · see citing works
Martelius, T., Jalava, J., Kärki, T., Möttönen, T., Ollgren, J. P., Lyytikäinen, O., & the Hospital Infection Surveillance team (2015) · Scandinavian Journal of Infectious Diseases · doi:10.3109/23744235.2015.1109135 · Cited by 60 · see citing works
Heteroresistance to carbapenems in invasive Pseudomonas aeruginosa infections
He, J., Jia, X., Yang, S., Xu, X., Sun, K., Li, C., Yang, T., & Zhang, L. (2017) · International Journal of Antimicrobial Agents · doi:10.1016/j.ijantimicag.2017.10.014 · Cited by 57 · see citing works
Lee, H.-Y., Chen, C., Wang, S.-B., et al. (2011) · International Journal of Antimicrobial Agents · doi:10.1016/j.ijantimicag.2010.12.015 · Cited by 56 · see citing works
Yang, D., Guo, Y., & Zheng, Z. (2009) · Current Microbiology · doi:10.1007/s00284-009-9364-4 · Cited by 52 · see citing works
Luo, Y., Yang, J., Zhang, Y., et al. (2011) · International Journal of Antimicrobial Agents · doi:10.1016/j.ijantimicag.2010.12.018 · Cited by 42 · see citing works
Ikonomidis, A., Tsakris, A., Καντζάνου, Μ., et al. (2008) · FEMS Microbiology Letters · doi:10.1111/j.1574-6968.2007.00997.x · Cited by 38 · see citing works
β -Lactamases- the Threat Renews
Livermore, D. M. (2009) · Current Protein and Peptide Science · doi:10.2174/138920309789351994 · Cited by 31 · see citing works
Tan, K. K., Nguyen, J., Nguyen, K., et al. (2020) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkaa048 · Cited by 26 · see citing works
Xu, H., Huo, C., Sun, Y., et al. (2018) · Infection and Drug Resistance · doi:10.2147/idr.s189494 · Cited by 18 · see citing works
Zhang, F., Ding, M., Yan, X., Bai, J., Li, Q., Zhang, B., Liang, Q., Liang, S., Wang, G., & Zhou, Y. (2021) · Microbial Pathogenesis · doi:10.1016/j.micpath.2021.105162 · Cited by 17 · see citing works
Self-citationGude, M. J., Seral, C., Sáenz, Y., et al. (2012) · European Journal of Clinical Microbiology & Infectious Diseases · doi:10.1007/s10096-011-1537-y · Cited by 15 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [1]O’Neill J. Tackling drug-resistant infections globally: final report and recommendations. The Review on Antimicrobial Resistance London, United Kingdom; 2016.
Cited by
Sorted by citations
Zhai, B., Liao, C., Jaggavarapu, S., Tang, Y., Rolling, T., Ning, Y., Sun, T., Bergin, S. A., Gjonbalaj, M., Miranda, E., et al. (2024) · Nature Medicine · doi:10.1038/s41591-024-03183-4 · Cited by 62 · see citing works
Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance
Su, Y., Li, Y., Yi, Q., Xu, Y., Sun, T., & Li, Y. (2025) · Journal of Fungi · doi:10.3390/jof11020143 · Cited by 18 · see citing works
- Authors
- Xiong, Y., Han, Y., Zhao, Z., Gao, W., Ma, Y., Jiang, S., Wang, M., Zhang, Q., Zhou, Y., & Chen, Y.
- Affiliations
- Dalian Medical University (CN)
- Corresponding author
- Chen, Yang
- Venue
- Infection and Drug Resistance
- Publisher
- Informa UK Limited
- Published
- 2021-12
- Volume
- Volume 14
- Pages
- 5639-5650
- ISSN
- 1178-6973 (ISSN-L)
- PMC
- PMC8711563
- OpenAlex
- W4200386557
- Cited by
- 22
- References
- 44
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 4 · 2023: 3 · 2022: 4
- FWCI
- 0.87
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Infection and Drug Resistance (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Dove Medical Press (Taylor and Francis Group) (submittedVersion, cc-by-nc)
- Funders
- National Natural Science Foundation of China (81401697)
- Natural Science Foundation of Liaoning Province (2019-MS-092)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
- Life Sciences › Immunology and Microbiology › Applied Microbiology and Biotechnology › Antibiotic Use and Resistance
- Health Sciences › Medicine › Infectious Diseases › Antimicrobial Resistance in Staphylococcus
- Keywords
- Klebsiella pneumoniae, multidrug resistance, extended-spectrum beta-lactamase, AmpC beta-lactamase, imipenem, population analysis profile, peritonitis, antibiotic treatment failure, mouse model, subgroup heterogeneity, molecular epidemiology
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