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However,\n              <jats:italic>in vitro<\/jats:italic>\n              studies indicate that these sorts of strains can mutate becoming MEM-resistant, raising concerns about the effectiveness of carbapenems as treatment option. We have studied mutation rates occurring from the reversion of MEM-susceptible KPC-114 to MEM-resistant KPC-2, in CZA-resistant\n              <jats:italic>K. pneumoniae<\/jats:italic>\n              belonging to ST11. Two-step fluctuation assays (FAs) were conducted. In brief, initial cultures of KPC-114-producing\n              <jats:italic>K. pneumoniae<\/jats:italic>\n              showing 1 \u00b5g\/mL MEM MIC were spread on Mueller\u2013Hinton agar plates containing 2\u20138 \u00b5g\/mL MEM. A second step of FA, at 4\u201316 \u00b5g\/mL MEM was performed from a mutant colony obtained at 2 \u00b5g\/mL MEM. Mutation rates were calculated using maximum likelihood estimation. Parental and mutant strains were sequenced by Illumina NextSeq, and mutations were predicted by variant-calling analysis. At 8 \u00b5g\/mL MEM, mutants derived from parental CZA-resistant (MIC \u2265 64 \u00b5g\/mL)\/MEM-susceptible (MIC = 1 \u00b5g\/mL) KPC-114-positive\n              <jats:italic>K. pneumoniae<\/jats:italic>\n              exhibited an accumulative mutation rate of 3.05 \u00d7 10\n              <jats:sup>\u221219<\/jats:sup>\n              mutations\/cell\/generation, whereas at 16 \u00b5g\/mL MEM an accumulative mutation rate of 1.33 \u00d7 10\n              <jats:sup>\u221219<\/jats:sup>\n              mutations\/cell\/generation resulted in the reversion of KPC-114 (S181_P182 deletion) to KPC-2. These findings highlight that the reversion of MEM-susceptible KPC-114 to MEM-resistant KPC-2, in CZA-resistant\n              <jats:italic>K. pneumoniae<\/jats:italic>\n              ST11 is related to low mutation rates suggesting a low risk of therapeutic failure.\n              <jats:italic>In vivo<\/jats:italic>\n              investigations are necessary to confirm the clinical potential of MEM against CZA-resistant KPC variants.\n            <\/jats:p>\n            <jats:sec>\n              <jats:title>IMPORTANCE<\/jats:title>\n              <jats:p>\n                The emergence of ceftazidime-avibactam (CZA) resistance among carbapenem-resistant\n                <jats:italic>Klebsiella pneumoniae<\/jats:italic>\n                is a major concern due to the limited therapeutic options. Strikingly, KPC mutations mediating CZA resistance are generally associated with meropenem susceptibility, suggesting a potential therapeutic use of this carbapenem antibiotic. However, the reversion of meropenem-susceptible to meropenem-resistant could be expected. Therefore, knowing the mutation rate related to this genetic event is essential to estimate the potential use of meropenem against CZA-resistant KPC-producing\n                <jats:italic>K. pneumoniae<\/jats:italic>\n                . In this study, we demonstrate,\n                <jats:italic>in vitro<\/jats:italic>\n                , that under high concentrations of meropenem, reversion of KPC-114 to KPC-2 in CZA-resistant\/meropenem-susceptible\n                <jats:italic>K. pneumoniae<\/jats:italic>\n                belonging to the global high-risk ST11 is related to low mutation rates.\n              <\/jats:p>\n            <\/jats:sec>\n          <\/jats:sec>","DOI":"10.1128\/spectrum.01173-24","type":"journal-article","created":{"date-parts":[[2024,8,27]],"date-time":"2024-08-27T17:29:50Z","timestamp":1724779790000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Reversion of KPC-114 to KPC-2 in ceftazidime-avibactam- resistant\/meropenem-susceptible\n            <i>Klebsiella pneumoniae<\/i>\n            ST11 is related to low mutation rates"],"prefix":"10.1128","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9174-0749","authenticated-orcid":false,"given":"Jesus G. M.","family":"Pariona","sequence":"first","affiliation":[{"name":"Department of Clinical Analysis, Faculty of Pharmaceutical Sciences, Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"},{"name":"One Health Brazilian Resistance Project (OneBR), S\u00e3o Paulo, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9447-8325","authenticated-orcid":false,"given":"Felipe","family":"V\u00e1squez-Ponce","sequence":"additional","affiliation":[{"name":"One Health Brazilian Resistance Project (OneBR), S\u00e3o Paulo, Brazil"},{"name":"Department of Microbiology, Instituto de Ci\u00eancias Biom\u00e9dicas II, Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johana","family":"Becerra","sequence":"additional","affiliation":[{"name":"One Health Brazilian Resistance Project (OneBR), S\u00e3o Paulo, Brazil"},{"name":"Department of Microbiology, Instituto de Ci\u00eancias Biom\u00e9dicas II, Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"},{"name":"Antimicrobial Resistance Institute of S\u00e3o Paulo (ARIES), S\u00e3o Paulo, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thais","family":"Martins-Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"One Health Brazilian Resistance Project (OneBR), S\u00e3o Paulo, Brazil"},{"name":"Department of Microbiology, Instituto de Ci\u00eancias Biom\u00e9dicas II, Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva M. M.","family":"Pariona","sequence":"additional","affiliation":[{"name":"Universidad Peruana Cayetano Heredia, Unidad de Investigaci\u00f3n de Enfermedades Emergentes y Cambio Clim\u00e1tico, San Mart\u00edn de Porres, Peru"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabio T.","family":"Madue\u00f1o","sequence":"additional","affiliation":[{"name":"Escola Polit\u00e9cnica, Engenharia El\u00e9trica, Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernanda","family":"Esposito","sequence":"additional","affiliation":[{"name":"Department of Clinical Analysis, Faculty of Pharmaceutical Sciences, Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"},{"name":"One Health Brazilian Resistance Project (OneBR), S\u00e3o Paulo, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aline","family":"V. de Lima","sequence":"additional","affiliation":[{"name":"Department of Clinical Analysis, Faculty of Pharmaceutical Sciences, Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7789-3028","authenticated-orcid":true,"given":"Jorge L.","family":"Mello Sampaio","sequence":"additional","affiliation":[{"name":"Department of Clinical Analysis, Faculty of Pharmaceutical Sciences, Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5686-9704","authenticated-orcid":true,"given":"Rodrigo S.","family":"Galhardo","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Instituto de Ci\u00eancias Biom\u00e9dicas II, Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0161-5800","authenticated-orcid":true,"given":"Nilton","family":"Lincopan","sequence":"additional","affiliation":[{"name":"Department of Clinical Analysis, Faculty of Pharmaceutical Sciences, Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"},{"name":"One Health Brazilian Resistance Project (OneBR), S\u00e3o Paulo, Brazil"},{"name":"Department of Microbiology, Instituto de Ci\u00eancias Biom\u00e9dicas II, Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"},{"name":"Antimicrobial Resistance Institute of S\u00e3o Paulo (ARIES), S\u00e3o Paulo, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmi.2019.11.011"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkz330"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.04105-23"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.00447-22"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.04111-23"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2024.107163"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/cmr.00008-23"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.02124-21"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.00374-23"},{"key":"e_1_3_3_11_2","unstructured":"The European Committee on Antimicrobial Susceptibility Testing. 2024. 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New KPC variants conferring ceftazidime-avibactam resistance and performance of the NG-Test CARBA-5 in its detection. 33rd ed. 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