What Contributes to the Minimum Inhibitory Concentration? Beyond β-Lactamase Gene Detection in Klebsiella pneumoniae
Abstract Background Klebsiella pneumoniae is capable of resistance to β-lactam antibiotics through expression of β-lactamases (both chromosomal and plasmid-encoded) and downregulation of outer membrane porins. However, the extent to which these mechanisms interplay in a resistant phenotype is not we...
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| Veröffentlicht in: | The Journal of infectious diseases 2024-10, Vol.230 (4), p.e777-e788 |
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| creator | Maclean, Alyssa K W Morrow, Stacey Niu, Fang Hanson, Nancy D |
| description | Abstract
Background
Klebsiella pneumoniae is capable of resistance to β-lactam antibiotics through expression of β-lactamases (both chromosomal and plasmid-encoded) and downregulation of outer membrane porins. However, the extent to which these mechanisms interplay in a resistant phenotype is not well understood. The purpose of this study was to determine the extent to which β-lactamases and outer membrane porins affected β-lactam resistance.
Methods
Minimum inhibitory concentrations (MICs) to β-lactams and inhibitor combinations were determined by agar dilution or Etest. Outer membrane porin production was evaluated by Western blot of outer membrane fractions. β-lactamase carriage was determined by whole genome sequencing and expression evaluated by real-time reverse-transcription polymerase chain reaction.
Results
Plasmid-encoded β-lactamases were important for cefotaxime and ceftazidime resistance. Elevated expression of chromosomal SHV was important for ceftolozane-tazobactam resistance. Loss of outer membrane porins was predictive of meropenem resistance. Extended-spectrum β-lactamases and plasmid-encoded AmpCs (pAmpCs) in addition to porin loss were sufficient to confer resistance to the third-generation cephalosporins, piperacillin-tazobactam, ceftolozane-tazobactam, and meropenem. pAmpCs (CMY-2 and DHA) alone conferred resistance to piperacillin-tazobactam.
Conclusions
Detection of a resistance gene by whole genome sequencing was not sufficient to predict resistance to all antibiotics tested. Some β-lactam resistance was dependent on the expression of both plasmid-encoded and chromosomal β-lactamases and loss of porins.
β-lactamases are the major resistance mechanism associated with β-lactam resistance. However, chromosomal β-lactamases and porins are important resistance mechanisms that contribute to the minimum inhibitory concentration (MIC). This article identifies the interplay among chromosomal and plasmid-encoded mechanisms and their contribution to the MIC.
Graphical Abstract
Graphical Abstract |
| doi_str_mv | 10.1093/infdis/jiae204 |
| format | Article |
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Background
Klebsiella pneumoniae is capable of resistance to β-lactam antibiotics through expression of β-lactamases (both chromosomal and plasmid-encoded) and downregulation of outer membrane porins. However, the extent to which these mechanisms interplay in a resistant phenotype is not well understood. The purpose of this study was to determine the extent to which β-lactamases and outer membrane porins affected β-lactam resistance.
Methods
Minimum inhibitory concentrations (MICs) to β-lactams and inhibitor combinations were determined by agar dilution or Etest. Outer membrane porin production was evaluated by Western blot of outer membrane fractions. β-lactamase carriage was determined by whole genome sequencing and expression evaluated by real-time reverse-transcription polymerase chain reaction.
Results
Plasmid-encoded β-lactamases were important for cefotaxime and ceftazidime resistance. Elevated expression of chromosomal SHV was important for ceftolozane-tazobactam resistance. Loss of outer membrane porins was predictive of meropenem resistance. Extended-spectrum β-lactamases and plasmid-encoded AmpCs (pAmpCs) in addition to porin loss were sufficient to confer resistance to the third-generation cephalosporins, piperacillin-tazobactam, ceftolozane-tazobactam, and meropenem. pAmpCs (CMY-2 and DHA) alone conferred resistance to piperacillin-tazobactam.
Conclusions
Detection of a resistance gene by whole genome sequencing was not sufficient to predict resistance to all antibiotics tested. Some β-lactam resistance was dependent on the expression of both plasmid-encoded and chromosomal β-lactamases and loss of porins.
β-lactamases are the major resistance mechanism associated with β-lactam resistance. However, chromosomal β-lactamases and porins are important resistance mechanisms that contribute to the minimum inhibitory concentration (MIC). This article identifies the interplay among chromosomal and plasmid-encoded mechanisms and their contribution to the MIC.
Graphical Abstract
Graphical Abstract</description><identifier>ISSN: 0022-1899</identifier><identifier>ISSN: 1537-6613</identifier><identifier>EISSN: 1537-6613</identifier><identifier>DOI: 10.1093/infdis/jiae204</identifier><identifier>PMID: 38654105</identifier><language>eng</language><publisher>US: Oxford University Press</publisher><subject>Antibiotics ; Cefotaxime ; Ceftazidime ; Cephalosporins ; Genomes ; Klebsiella pneumoniae ; Major ; Meropenem ; Minimum inhibitory concentration ; Phenotypes ; Piperacillin-tazobactam ; Porins ; Whole genome sequencing ; β Lactamase ; β-Lactam antibiotics</subject><ispartof>The Journal of infectious diseases, 2024-10, Vol.230 (4), p.e777-e788</ispartof><rights>The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. 2024</rights><rights>The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c275t-7e3bbe982ee97fd9dfaf2f7c263140953975929e2362a892ecaec6c7467a91343</cites><orcidid>0000-0001-7076-5875</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,1583,27923,27924</link.rule.ids></links><search><creatorcontrib>Maclean, Alyssa K W</creatorcontrib><creatorcontrib>Morrow, Stacey</creatorcontrib><creatorcontrib>Niu, Fang</creatorcontrib><creatorcontrib>Hanson, Nancy D</creatorcontrib><title>What Contributes to the Minimum Inhibitory Concentration? Beyond β-Lactamase Gene Detection in Klebsiella pneumoniae</title><title>The Journal of infectious diseases</title><description>Abstract
Background
Klebsiella pneumoniae is capable of resistance to β-lactam antibiotics through expression of β-lactamases (both chromosomal and plasmid-encoded) and downregulation of outer membrane porins. However, the extent to which these mechanisms interplay in a resistant phenotype is not well understood. The purpose of this study was to determine the extent to which β-lactamases and outer membrane porins affected β-lactam resistance.
Methods
Minimum inhibitory concentrations (MICs) to β-lactams and inhibitor combinations were determined by agar dilution or Etest. Outer membrane porin production was evaluated by Western blot of outer membrane fractions. β-lactamase carriage was determined by whole genome sequencing and expression evaluated by real-time reverse-transcription polymerase chain reaction.
Results
Plasmid-encoded β-lactamases were important for cefotaxime and ceftazidime resistance. Elevated expression of chromosomal SHV was important for ceftolozane-tazobactam resistance. Loss of outer membrane porins was predictive of meropenem resistance. Extended-spectrum β-lactamases and plasmid-encoded AmpCs (pAmpCs) in addition to porin loss were sufficient to confer resistance to the third-generation cephalosporins, piperacillin-tazobactam, ceftolozane-tazobactam, and meropenem. pAmpCs (CMY-2 and DHA) alone conferred resistance to piperacillin-tazobactam.
Conclusions
Detection of a resistance gene by whole genome sequencing was not sufficient to predict resistance to all antibiotics tested. Some β-lactam resistance was dependent on the expression of both plasmid-encoded and chromosomal β-lactamases and loss of porins.
β-lactamases are the major resistance mechanism associated with β-lactam resistance. However, chromosomal β-lactamases and porins are important resistance mechanisms that contribute to the minimum inhibitory concentration (MIC). This article identifies the interplay among chromosomal and plasmid-encoded mechanisms and their contribution to the MIC.
Graphical Abstract
Graphical Abstract</description><subject>Antibiotics</subject><subject>Cefotaxime</subject><subject>Ceftazidime</subject><subject>Cephalosporins</subject><subject>Genomes</subject><subject>Klebsiella pneumoniae</subject><subject>Major</subject><subject>Meropenem</subject><subject>Minimum inhibitory concentration</subject><subject>Phenotypes</subject><subject>Piperacillin-tazobactam</subject><subject>Porins</subject><subject>Whole genome sequencing</subject><subject>β Lactamase</subject><subject>β-Lactam antibiotics</subject><issn>0022-1899</issn><issn>1537-6613</issn><issn>1537-6613</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>TOX</sourceid><recordid>eNqFkUFv1DAQhS1ERZfClbMlLnBIa3sSOz5VdIFSsYgLiKPlOBPWq8ReYgdp_1Z_CL-JrLJCopdKI81hvnl6T4-QV5xdcqbhyoeu9elq5y0KVj4hK16BKqTk8JSsGBOi4LXW5-R5SjvGWAlSPSPnUMuq5KxakenH1ma6jiGPvpkyJpojzVukX3zwwzTQu7D1jc9xPBwphzNos4_hmt7gIYaW_rkvNtZlO9iE9BYD0veY0R0Z6gP93GOTPPa9pfuA0xDDbPUFOetsn_DlaV-Q7x8_fFt_KjZfb-_W7zaFE6rKhUJoGtS1QNSqa3Xb2U50ygkJvGS6Aq0qLTQKkMLWWqCz6KRTpVRWcyjhglwvuvupGbBd3PdmP_rBjgcTrTf_X4Lfmp_xt-G8rOepZ4U3J4Ux_powZTP45I5xAsYpGWBlxTkokDP6-gG6i9MY5nwGOEAFkik9U5cL5caY0ojdPzecmWOlZqnUnCqdH94uD3HaP8b-Bbq8phY</recordid><startdate>20241016</startdate><enddate>20241016</enddate><creator>Maclean, Alyssa K W</creator><creator>Morrow, Stacey</creator><creator>Niu, Fang</creator><creator>Hanson, Nancy D</creator><general>Oxford University Press</general><scope>TOX</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-7076-5875</orcidid></search><sort><creationdate>20241016</creationdate><title>What Contributes to the Minimum Inhibitory Concentration? Beyond β-Lactamase Gene Detection in Klebsiella pneumoniae</title><author>Maclean, Alyssa K W ; Morrow, Stacey ; Niu, Fang ; Hanson, Nancy D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c275t-7e3bbe982ee97fd9dfaf2f7c263140953975929e2362a892ecaec6c7467a91343</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Antibiotics</topic><topic>Cefotaxime</topic><topic>Ceftazidime</topic><topic>Cephalosporins</topic><topic>Genomes</topic><topic>Klebsiella pneumoniae</topic><topic>Major</topic><topic>Meropenem</topic><topic>Minimum inhibitory concentration</topic><topic>Phenotypes</topic><topic>Piperacillin-tazobactam</topic><topic>Porins</topic><topic>Whole genome sequencing</topic><topic>β Lactamase</topic><topic>β-Lactam antibiotics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Maclean, Alyssa K W</creatorcontrib><creatorcontrib>Morrow, Stacey</creatorcontrib><creatorcontrib>Niu, Fang</creatorcontrib><creatorcontrib>Hanson, Nancy D</creatorcontrib><collection>Oxford Journals Open Access Collection</collection><collection>CrossRef</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of infectious diseases</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Maclean, Alyssa K W</au><au>Morrow, Stacey</au><au>Niu, Fang</au><au>Hanson, Nancy D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>What Contributes to the Minimum Inhibitory Concentration? Beyond β-Lactamase Gene Detection in Klebsiella pneumoniae</atitle><jtitle>The Journal of infectious diseases</jtitle><date>2024-10-16</date><risdate>2024</risdate><volume>230</volume><issue>4</issue><spage>e777</spage><epage>e788</epage><pages>e777-e788</pages><issn>0022-1899</issn><issn>1537-6613</issn><eissn>1537-6613</eissn><abstract>Abstract
Background
Klebsiella pneumoniae is capable of resistance to β-lactam antibiotics through expression of β-lactamases (both chromosomal and plasmid-encoded) and downregulation of outer membrane porins. However, the extent to which these mechanisms interplay in a resistant phenotype is not well understood. The purpose of this study was to determine the extent to which β-lactamases and outer membrane porins affected β-lactam resistance.
Methods
Minimum inhibitory concentrations (MICs) to β-lactams and inhibitor combinations were determined by agar dilution or Etest. Outer membrane porin production was evaluated by Western blot of outer membrane fractions. β-lactamase carriage was determined by whole genome sequencing and expression evaluated by real-time reverse-transcription polymerase chain reaction.
Results
Plasmid-encoded β-lactamases were important for cefotaxime and ceftazidime resistance. Elevated expression of chromosomal SHV was important for ceftolozane-tazobactam resistance. Loss of outer membrane porins was predictive of meropenem resistance. Extended-spectrum β-lactamases and plasmid-encoded AmpCs (pAmpCs) in addition to porin loss were sufficient to confer resistance to the third-generation cephalosporins, piperacillin-tazobactam, ceftolozane-tazobactam, and meropenem. pAmpCs (CMY-2 and DHA) alone conferred resistance to piperacillin-tazobactam.
Conclusions
Detection of a resistance gene by whole genome sequencing was not sufficient to predict resistance to all antibiotics tested. Some β-lactam resistance was dependent on the expression of both plasmid-encoded and chromosomal β-lactamases and loss of porins.
β-lactamases are the major resistance mechanism associated with β-lactam resistance. However, chromosomal β-lactamases and porins are important resistance mechanisms that contribute to the minimum inhibitory concentration (MIC). This article identifies the interplay among chromosomal and plasmid-encoded mechanisms and their contribution to the MIC.
Graphical Abstract
Graphical Abstract</abstract><cop>US</cop><pub>Oxford University Press</pub><pmid>38654105</pmid><doi>10.1093/infdis/jiae204</doi><orcidid>https://orcid.org/0000-0001-7076-5875</orcidid><oa>free_for_read</oa></addata></record> |
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| source | Oxford University Press Journals All Titles (1996-Current) |
| subjects | Antibiotics Cefotaxime Ceftazidime Cephalosporins Genomes Klebsiella pneumoniae Major Meropenem Minimum inhibitory concentration Phenotypes Piperacillin-tazobactam Porins Whole genome sequencing β Lactamase β-Lactam antibiotics |
| title | What Contributes to the Minimum Inhibitory Concentration? Beyond β-Lactamase Gene Detection in Klebsiella pneumoniae |
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