Carbapenem-resistant K. pneumoniae exhibiting clinically undetected amikacin and meropenem heteroresistance leads to treatment failure in a murine model of infection
Abstract
Heteroresistance is a poorly understood mechanism of resistance which refers to a phenomenon where there are different subpopulations of seemingly isogenic bacteria which exhibit a range of susceptibilities to a particular antibiotic. In the current study, we identified a multidrug-resistant, carbapenemase-positive K. pneumoniae strain SWMUF35 which was classified as susceptible to amikacin and resistant to meropenem by clinical diagnostics yet harbored different subpopulations of phenotypically resistant cells, and has the ability to form biofilm. Population analysis profile (PAP) indicated that SWMUF35 showed heteroresistance towards amikacin and meropenem which was considered as co-heteroresistant K. pneumoniae strain. In vitro experiments such as dual PAP, dual Times-killing assays and checkerboard assay showed that antibiotic combination therapy (amikacin combined with meropenem) can effectively combat SWMUF35. Importantly, using an in vivo mouse model of peritonitis, we found that amikacin or meropenem monotherapy was unable to rescue mice infected with SWMUF35. Antibiotic combination therapy could be a rational strategy to use clinically approved antibiotics when monotherapy would fail. Furthermore, our data warn that antibiotic susceptibility testing results may be unreliable due to undetected heteroresistance which can lead to treatment failure and the detection of this phenotype is a prerequisite for a proper choice of antibiotic to support a successful treatment outcome.
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An in vivo experiment with K. pneumoniae strain SWMUF35-infected mice showed contradictory results compared to in vitro experiments, which classified the strain as amikacin susceptible.
“An in vivo experiment with K. pneumoniae strain SWMUF35-infected mice showed contradictory results compared to in vitro experiments, which classified the strain as amikacin susceptible [28].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [28]
For diagnosed fungal infections, antifungal heteroresistance may lead to persistent infections that require longer or more aggressive treatment regimens.
“For diagnosed fungal infections, it may lead to persistent infections that require longer or more aggressive treatment regimens [27,28,29,30].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [28]
For bacteria, combination of several antibiotics serves as preferred strategy.
“For bacteria, a combination of several antibiotics serves as the preferred strategy [28,174,175,176].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [28]
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- Authors
- Zhang, F., Ding, M., Yan, X., Bai, J., Li, Q., Zhang, B., Liang, Q., Liang, S., Wang, G., & Zhou, Y.
- Affiliations
- Southwest Medical University (CN)
- Corresponding author
- Zhou, Yingshun
- Venue
- Microbial Pathogenesis
- Publisher
- Elsevier BV
- Published
- 2021-11
- Volume
- 160
- Pages
- 105162
- ISSN
- 0882-4010 (ISSN-L)
- OpenAlex
- W3198358613
- Cited by
- 17
- References
- 19
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 1 · 2023: 2 · 2022: 4 · 2021: 2
- FWCI
- 0.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Microbial Pathogenesis (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Sichuan Province Science and Technology Support Program (2020YJ0338)
- National Natural Science Foundation of China (31500114)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Bacterial Identification and Susceptibility Testing
- Health Sciences › Medicine › Infectious Diseases › Antimicrobial Resistance in Staphylococcus
- Keywords
- carbapenem-resistant Klebsiella pneumoniae, heteroresistance, amikacin, meropenem, carbapenemase, multidrug resistance, combination antibiotic therapy, antimicrobial susceptibility testing, population analysis profile, biofilm formation, peritonitis, treatment failure, mouse infection model
- MeSH terms
- Meropenem, Amikacin, Animals, Anti-Bacterial Agents, Disease Models, Animal, Klebsiella pneumoniae, Microbial Sensitivity Tests, Carbapenems, Treatment Failure, Mice
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