{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T21:17:49Z","timestamp":1767647869352,"version":"3.48.0"},"reference-count":38,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T00:00:00Z","timestamp":1767571200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003593","name":"National Council for Scientific and Technological Development","doi-asserted-by":"crossref","award":["408778\/2022-9, 307946\/2022-3, 444735\/2023-2 and 405785\/2024-0"],"award-info":[{"award-number":["408778\/2022-9, 307946\/2022-3, 444735\/2023-2 and 405785\/2024-0"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Foundation to Support the Development of Education, Science and Technology of the State of Mato Grosso do Sul","award":["76\/2023 and 113\/2023"],"award-info":[{"award-number":["76\/2023 and 113\/2023"]}]},{"DOI":"10.13039\/501100002322","name":"Coordination for the Improvement of Higher Education Personnel","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100020983","name":"Federal University of Grande Dourados","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100020983","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>\n                      This study aimed to evaluate the toxicity and antibacterial efficacy of Cefotaxime\/Polymyxin B combination (CTX\/PMB) against a polymyxin-carbapenem-resistant (PC-R)\n                      <jats:italic>Klebsiella pneumoniae<\/jats:italic>\n                      strain, using a mice model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>\n                      A single-dose toxicity assay was conducted in BALB\/c mice, divided into control and CTX\/PMB-treated groups receiving low, medium, or high CTX doses. Body weight, food, and water intake were monitored for 14 days. After euthanasia, organ weights and plasma biochemical markers were analyzed. Medium- and high-dose groups maintained stable weight and intake. High-dose mice exhibited reduced right kidney and liver weights and elevated urea levels. Creatinine was at the upper limit in all groups, including one control mouse. For antimicrobial efficacy, BALB\/c neutropenic mice infected with PC-R\n                      <jats:italic>K. pneumoniae<\/jats:italic>\n                      K18 were assigned to na\u00efve, mock-treated, CTX, PMB, or CTX\/PMB groups. Treatments were given every 12 h, and after 24 h, blood was collected to quantify bacterial load. CTX\/PMB significantly reduced blood bacterial load and improved clinical condition compared to other groups.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      CTX\/PMB showed therapeutic potential in treating PC-R\n                      <jats:italic>K. pneumoniae<\/jats:italic>\n                      . However higher CTX doses may potentiate PMB-associated toxicity. These findings encourage further investigation in advanced preclinical models and clinical settings to fully elucidate CTX\/PMB therapeutic potential and optimize dosing regimens.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0339990","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T19:10:36Z","timestamp":1767640236000},"page":"e0339990","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Safety and therapeutic potential evaluation of Cefotaxime plus Polymyxin B against polymyxin-carbapenem resistant Klebsiella pneumoniae in a murine model"],"prefix":"10.1371","volume":"21","author":[{"given":"Mariana Carvalho","family":"Sturaro","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathalia da Silva","family":"Damaceno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gleyce Hellen de Almeida","family":"de Souza","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9 Eduardo Souza","family":"Echeverria","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ediane Bortolotte","family":"Cornelius","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luccas Pereira","family":"Pires","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pedro Vin\u00edcius Dias Bassetto","family":"Silva","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B\u00e1rbara Maria Cristaldo","family":"Gomes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thiago Leite","family":"Fraga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Osmar Nascimento","family":"Silva","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luana","family":"Rossato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2367-0915","authenticated-orcid":true,"given":"Simone","family":"Simionatto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,1,5]]},"reference":[{"issue":"1","key":"pone.0339990.ref001","doi-asserted-by":"crossref","first-page":"100947","DOI":"10.1016\/j.lanmic.2024.07.010","article-title":"Antimicrobial resistance: a concise update","volume":"6","author":"CS Ho","year":"2025","journal-title":"Lancet Microbe"},{"issue":"3","key":"pone.0339990.ref002","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/S1473-3099(21)00399-6","article-title":"Clinical outcomes and bacterial characteristics of carbapenem-resistant Klebsiella pneumoniae complex among patients from different global regions (CRACKLE-2): a prospective, multicentre, cohort study","volume":"22","author":"M Wang","year":"2022","journal-title":"Lancet Infect Dis"},{"issue":"4","key":"pone.0339990.ref003","doi-asserted-by":"crossref","first-page":"208","DOI":"10.12731\/2658-6649-2024-16-4-1249","article-title":"First report of co-harboring bleomycin resistance gene (bleMBL) and carbapenemase resistance gene (blaNDM-1) Klebsiella pneumoniae in Iraq with comparison study among the sensitivity test, the BD Phoenix CPO detect test, and the Rapidec\u00ae Carba NP test","volume":"16","author":"SA Hasan","year":"2024","journal-title":"SJLSA"},{"issue":"5","key":"pone.0339990.ref004","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1080\/1040841X.2024.2313024","article-title":"Antibiotic resistance: a global crisis, problems and solutions","volume":"50","author":"R Aggarwal","year":"2024","journal-title":"Crit Rev Microbiol"},{"issue":"2","key":"pone.0339990.ref005","doi-asserted-by":"crossref","first-page":"267","DOI":"10.15421\/022439","article-title":"Antibacterial activity of deer musk and Ziziphus spina-christi against carbapebem resis-tant gram negative bacteria isolated from patients with burns and wounds","volume":"15","author":"SA Hasan","year":"2024","journal-title":"Regul Mech Biosyst"},{"issue":"1","key":"pone.0339990.ref006","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1080\/14787210.2020.1705155","article-title":"Antibiotic combination therapy against resistant bacterial infections: synergy, rejuvenation and resistance reduction","volume":"18","author":"ARM Coates","year":"2020","journal-title":"Expert Rev Anti Infect Ther"},{"issue":"5","key":"pone.0339990.ref007","doi-asserted-by":"crossref","first-page":"106582","DOI":"10.1016\/j.ijantimicag.2022.106582","article-title":"Repurposing non-antibiotic drugs auranofin and pentamidine in combination to combat multidrug-resistant gram-negative bacteria","volume":"59","author":"Y Yu","year":"2022","journal-title":"Int J Antimicrob Agents"},{"issue":"1","key":"pone.0339990.ref008","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1186\/s12866-025-03914-8","article-title":"Investigation of the in vitro antimicrobial activity of eravacycline alone and in combination with various antibiotics against MDR Acinetobacter baumanni strains","volume":"25","author":"M Ataman","year":"2025","journal-title":"BMC Microbiol"},{"issue":"4","key":"pone.0339990.ref009","doi-asserted-by":"crossref","DOI":"10.1128\/aac.01483-24","article-title":"Combination therapy delays antimicrobial resistance after adaptive laboratory evolution of Staphylococcus aureus","volume":"69","author":"ME Petersen","year":"2025","journal-title":"Antimicrob Agents Chemother"},{"issue":"20","key":"pone.0339990.ref010","doi-asserted-by":"crossref","first-page":"15493","DOI":"10.3390\/ijms242015493","article-title":"The combination of antibiotic and non-antibiotic compounds improves antibiotic efficacy against multidrug-resistant bacteria","volume":"24","author":"G Xiao","year":"2023","journal-title":"Int J Mol Sci"},{"issue":"2","key":"pone.0339990.ref011","doi-asserted-by":"crossref","first-page":"341","DOI":"10.3201\/eid2902.221066","article-title":"Penicillin and cefotaxime resistance of quinolone-resistant Neisseria meningitidis clonal complex 4821, Shanghai, China, 1965-2020","volume":"29","author":"M Chen","year":"2023","journal-title":"Emerg Infect Dis"},{"issue":"3","key":"pone.0339990.ref012","article-title":"Phenotypic and molecular characterization of ESBL producing Escherichia coli and Klebsiella pneumoniae among Lebanese patients","volume":"5","author":"SA El-Hariri","year":"2023","journal-title":"JAC Antimicrob Resist"},{"issue":"3","key":"pone.0339990.ref013","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/s41429-023-00687-y","article-title":"Cephalosporin resistance, tolerance, and approaches to improve their activities","volume":"77","author":"AH Araten","year":"2024","journal-title":"J Antibiot (Tokyo)"},{"issue":"8","key":"pone.0339990.ref014","doi-asserted-by":"crossref","first-page":"1882","DOI":"10.1093\/jac\/dkad177","article-title":"Cefotaxime\/sulbactam plus gentamicin as a potential carbapenem- and amikacin-sparing first-line combination for neonatal sepsis in high ESBL prevalence settings","volume":"78","author":"JB Readman","year":"2023","journal-title":"J Antimicrob Chemother"},{"issue":"5","key":"pone.0339990.ref015","doi-asserted-by":"crossref","first-page":"2315","DOI":"10.1007\/s00431-023-04917-1","article-title":"Deep cervical abscesses in children: efficacy of the cefotaxime-rifampicin combination","volume":"182","author":"C Bory","year":"2023","journal-title":"Eur J Pediatr"},{"issue":"2","key":"pone.0339990.ref016","doi-asserted-by":"crossref","first-page":"158","DOI":"10.37201\/req\/107.2023","article-title":"Efficacy of delafloxacin alone and in combination with cefotaxime against cefotaxime non-susceptible invasive isolates of Streptococcus pneumoniae","volume":"37","author":"E R\u00edos","year":"2024","journal-title":"Rev Esp Quimioter"},{"issue":"10","key":"pone.0339990.ref017","doi-asserted-by":"crossref","DOI":"10.1128\/aac.00930-24","article-title":"Synergistic antimicrobial combination of third-generation cephalosporins and polymyxin B against carbapenem-polymyxin-resistant Klebsiella pneumoniae: an in vitro and in vivo analysis","volume":"68","author":"MC Sturaro","year":"2024","journal-title":"Antimicrob Agents Chemother"},{"issue":"1","key":"pone.0339990.ref018","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s12916-022-02719-0","article-title":"Recommendations for robust and reproducible preclinical research in personalised medicine","volume":"21","author":"V Fosse","year":"2023","journal-title":"BMC Med"},{"issue":"6","key":"pone.0339990.ref019","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1007\/s12149-021-01612-9","article-title":"Extended single-dose toxicity study of [211At]NaAt in mice for the first-in-human clinical trial of targeted alpha therapy for differentiated thyroid cancer","volume":"35","author":"T Watabe","year":"2021","journal-title":"Ann Nucl Med"},{"key":"pone.0339990.ref020","article-title":"Cefotaxime.","volume-title":"StatPearls","author":"IS Padda","year":"2025"},{"issue":"9","key":"pone.0339990.ref021","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1016\/j.cmi.2023.05.018","article-title":"A population pharmacokinetic model of polymyxin B based on prospective clinical data to inform dosing in hospitalized patients","volume":"29","author":"PO Hanafin","year":"2023","journal-title":"Clin Microbiol Infect"},{"key":"pone.0339990.ref022","doi-asserted-by":"crossref","first-page":"5515478","DOI":"10.1155\/2021\/5515478","article-title":"Single-Dose Toxicity Study on ML171, a Selective NOX1 Inhibitor, in Mice","volume":"2021","author":"S-H Oh","year":"2021","journal-title":"Biomed Res Int"},{"issue":"4","key":"pone.0339990.ref023","doi-asserted-by":"crossref","first-page":"630","DOI":"10.3390\/antibiotics12040630","article-title":"Predicting the area under the plasma concentration-time curve (AUC) for first dose vancomycin using first-order pharmacokinetic equations","volume":"12","author":"K Sujjavorakul","year":"2023","journal-title":"Antibiotics (Basel)"},{"issue":"14","key":"pone.0339990.ref024","doi-asserted-by":"crossref","first-page":"14271","DOI":"10.1021\/acsomega.5c00423","article-title":"Preclinical safety assessment and serum lipid profiles of wister rats following acute and subchronic exposure to water-soluble curcuminoid-rich extracts","volume":"10","author":"A Issuriya","year":"2025","journal-title":"ACS Omega"},{"issue":"2","key":"pone.0339990.ref025","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0319464","article-title":"Acute and sub-acute toxicity of ethanol extracts of Hagenia abyssinica and Rumex abyssinicus flowers in Swiss albino mice","volume":"20","author":"HB Gemeda","year":"2025","journal-title":"PLoS One"},{"issue":"7","key":"pone.0339990.ref026","doi-asserted-by":"crossref","first-page":"151448","DOI":"10.1016\/j.ijmm.2020.151448","article-title":"Molecular and epidemiological surveillance of polymyxin-resistant Klebsiella pneumoniae strains isolated from Brazil with multiple mgrB gene mutations","volume":"310","author":"KE da Silva","year":"2020","journal-title":"Int J Med Microbiol"},{"issue":"1","key":"pone.0339990.ref027","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1093\/jac\/dkae382","article-title":"Antimicrobial activity of ceftibuten\/polymyxin B combination against polymyxin\/carbapenem-resistant Klebsiella pneumoniae","volume":"80","author":"MC Sturaro","year":"2025","journal-title":"J Antimicrob Chemother"},{"key":"pone.0339990.ref028","doi-asserted-by":"crossref","first-page":"975066","DOI":"10.3389\/fphar.2022.975066","article-title":"Pharmacokinetics\/pharmacodynamics of polymyxin B in patients with bloodstream infection caused by carbapenem-resistant Klebsiella pneumoniae","volume":"13","author":"Z Yu","year":"2022","journal-title":"Front Pharmacol"},{"issue":"1","key":"pone.0339990.ref029","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1186\/s40635-024-00667-y","article-title":"An early and stable mouse model of polymyxin-induced acute kidney injury","volume":"12","author":"L Liu","year":"2024","journal-title":"Intensive Care Med Exp"},{"issue":"3","key":"pone.0339990.ref030","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1038\/s41429-019-0262-0","article-title":"Design, synthesis and antimicrobial studies of some polymyxin analogues","volume":"73","author":"H Tang","year":"2020","journal-title":"J Antibiot (Tokyo)"},{"issue":"4","key":"pone.0339990.ref031","article-title":"Polymyxin B nonapeptide potentiates the eradication of Gram-negative bacterial persisters","volume":"12","author":"SJ Kim","year":"2024","journal-title":"Microbiol Spectr"},{"issue":"2","key":"pone.0339990.ref032","first-page":"198","article-title":"Associations between clinical signs and pathological findings in toxicity testing","volume":"38","author":"AV Silva","year":"2021","journal-title":"ALTEX"},{"issue":"1","key":"pone.0339990.ref033","doi-asserted-by":"crossref","DOI":"10.1152\/ajprenal.00029.2024","article-title":"Mechanisms of gelofusine protection in an in vitro model of polymyxin B-associated renal injury","volume":"327","author":"CS Hudson","year":"2024","journal-title":"Am J Physiol Renal Physiol"},{"issue":"6","key":"pone.0339990.ref034","doi-asserted-by":"crossref","first-page":"622","DOI":"10.3390\/antibiotics14060622","article-title":"The effect of antibiotics on the nervous system: importance for anesthesiology and intensive care","volume":"14","author":"P Radkowski","year":"2025","journal-title":"Antibiotics"},{"key":"pone.0339990.ref035","doi-asserted-by":"crossref","first-page":"4657","DOI":"10.2147\/IDR.S334200","article-title":"In vitro and in vivo activity of combinations of polymyxin B with other antimicrobials against carbapenem-resistant Acinetobacter baumannii","volume":"14","author":"H Zhang","year":"2021","journal-title":"Infect Drug Resist"},{"issue":"5","key":"pone.0339990.ref036","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1093\/jac\/dkaf056","article-title":"The synergistic effect of the combination of polymyxin B and rifampicin in a murine neutropenic thigh infection model with E. coli and K. pneumoniae","volume":"80","author":"S Van Den Berg","year":"2025","journal-title":"J Antimicrob Chemother"},{"key":"pone.0339990.ref037","doi-asserted-by":"crossref","first-page":"727170","DOI":"10.3389\/fphar.2021.727170","article-title":"Population pharmacokinetics of polymyxin B and dosage optimization in renal transplant patients","volume":"12","author":"Y Li","year":"2021","journal-title":"Front Pharmacol"},{"issue":"4","key":"pone.0339990.ref038","doi-asserted-by":"crossref","first-page":"313","DOI":"10.3390\/antibiotics13040313","article-title":"Dosing regimen for cefotaxime should be adapted to the stage of renal dysfunction in critically ill adult patients-a retrospective study","volume":"13","author":"T Dillies","year":"2024","journal-title":"Antibiotics (Basel)"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0339990","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T19:10:43Z","timestamp":1767640243000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0339990"}},"subtitle":[],"editor":[{"given":"Tombari Pius","family":"Monsi","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2026,1,5]]},"references-count":38,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1,5]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0339990","relation":{},"ISSN":["1932-6203"],"issn-type":[{"type":"electronic","value":"1932-6203"}],"subject":[],"published":{"date-parts":[[2026,1,5]]}}}