{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T22:31:17Z","timestamp":1792276277952,"version":"4.4.0"},"reference-count":80,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T00:00:00Z","timestamp":1750032000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Br J Clin Pharmacol"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>The aim of this study was to elucidate the risk factors associated with the development of cefepime\u2010induced neurotoxicity (CIN).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This systematic review utilized keywords \u201ccefepime\u201d and \u201cneurotoxicity\u201d, sourced from PubMed, Scopus, Web of Science and Google Scholar. Meta\u2010analysis was conducted using a random effects model utilizing Mantel\u2013Haenszel and inverse variance analysis for dichotomous and continuous outcomes, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Analysis of 23 articles revealed that estimated glomerular filtration rate (eGFR)\u2009&lt;\u200930\u2009mL\/min\/1.73\u2009m<jats:sup>2<\/jats:sup> is the primary factor in CIN, with an odds ratio of 10.06 (95% confidence interval [CI]\u2009=\u20095.05\u201320.03, <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.0001). Other significant factors include central nervous system (CNS) abnormalities, age, body weight, albumin levels, diabetes mellitus, hypertension, chronic lung disease and inappropriate dosing. Subgroup analysis of continuous cefepime infusion utilization, based on several risk factors, indicated a lower odds ratio in comparison to intermittent infusion. For cefepime therapeutic drug monitoring (TDM) to determine potential CIN cases, the proposed trough concentration (<jats:italic>C<\/jats:italic><jats:sub>trough<\/jats:sub>) threshold for intermittent infusion is 20\u2009mg\/L, while the steady\u2010state concentration (<jats:italic>C<\/jats:italic><jats:sub>ss<\/jats:sub>) threshold for continuous infusion is 63\u2009mg\/L.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Numerous risk factors are significantly associated with CIN, with renal impairment being the most significant. Continuous cefepime infusion is a potential strategy to mitigate CIN, in addition to dose adjustment and TDM.<\/jats:p><\/jats:sec>","DOI":"10.1002\/bcp.70120","type":"journal-article","created":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T21:48:23Z","timestamp":1750110503000},"page":"2192-2204","source":"Crossref","is-referenced-by-count":10,"title":["Unveiling predisposing factors for cefepime\u2010induced neurotoxicity: A systematic review and meta\u2010analysis"],"prefix":"10.1002","volume":"91","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8940-9907","authenticated-orcid":false,"given":"Harri","family":"Hardi","sequence":"first","affiliation":[{"name":"Clinical Pharmacology Specialist Study Program, Faculty of Medicine Universitas Indonesia  Jakarta Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melva","family":"Louisa","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Faculty of Medicine Universitas Indonesia  Jakarta Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Indah Suci","family":"Widyahening","sequence":"additional","affiliation":[{"name":"Department of Community Medicine, Faculty of Medicine Universitas Indonesia  Jakarta Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia Remi","family":"Chandra","sequence":"additional","affiliation":[{"name":"Neurology Specialist Study Program, Faculty of Medicine Universitas Indonesia  Jakarta Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liganda Endo","family":"Mahata","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Specialist Study Program, Faculty of Medicine Universitas Indonesia  Jakarta Indonesia"},{"name":"Department of Pharmacology and Therapy, Faculty of Medicine Universitas Andalas  West Sumatra Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian","family":"Soetikno","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Faculty of Medicine Universitas Indonesia  Jakarta Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anggi","family":"Gayatri","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Faculty of Medicine Universitas Indonesia  Jakarta Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Instiaty","family":"Instiaty","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Faculty of Medicine Universitas Indonesia  Jakarta Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,6,16]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciaa373"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2019.01.018"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12028\u2010022\u201001442\u20101"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofx170"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13054\u2010017\u20101856\u20101"},{"key":"e_1_2_8_7_1","volume-title":"FDA drug safety communication: cefepime and risk of seizure in patients not receiving dosage adjustments for kidney impairment","author":"Food and Drug Administration","year":"2019"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.39.1.232"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms9071505"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkac271"},{"issue":"6","key":"e_1_2_8_11_1","article-title":"The trend of cefepime\u2010induced neurotoxicity: a systematic review","volume":"15","author":"Ajibola O","year":"2023","journal-title":"Cureus"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.n71"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.3310\/hta7270"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1177\/09622802231172043"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.2287"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.d4002"},{"issue":"2","key":"e_1_2_8_17_1","first-page":"S145","article-title":"The concise guide to PHARMACOLOGY 2023\/24: ion channels","volume":"180","author":"Alexander SPH","year":"2023","journal-title":"Br J Pharmacol"},{"issue":"2","key":"e_1_2_8_18_1","first-page":"S374","article-title":"The concise guide to PHARMACOLOGY 2023\/24: transporters","volume":"180","author":"Alexander SPH","year":"2023","journal-title":"Br J Pharmacol"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1186\/cc13094"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics12010069"},{"issue":"6","key":"e_1_2_8_21_1","first-page":"86","article-title":"Cefepime\u2010induced neurotoxicity in non\u2010critically ill medical patients: a retrospective cohort study","volume":"20","author":"Almulhim AS","year":"2024","journal-title":"Signa Vitae\u2010J Anesthesiol"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/jacamr\/dlac043"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2021.106472"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2017.03.018"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01595\u201008"},{"issue":"4","key":"e_1_2_8_26_1","first-page":"526","article-title":"Renal failure is a risk factor for cefepime\u2010induced encephalopathy","volume":"21","author":"Garces EO","year":"2008","journal-title":"J Nephrol"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.3109\/00365548.2013.878032"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmi.2017.01.005"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmi.2019.06.028"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.33879\/AMH.2019.125-1805.010"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkz476"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12028\u2010019\u201000682\u2010y"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.3988\/jcn.2020.16.3.408"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmi.2020.07.003"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2021.106443"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/phar.2744"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.2174\/1574886317666220309090408"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.14309\/01.ajg.0000955144.38705.93"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.ccm.0001000660.23432.12"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1177\/08971900241273163"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262\u2010022\u201001137\u2010y"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1177\/8755122520967398"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11695\u2010011\u20100586\u20108"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1097\/WNP.0b013e3182a73db9"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2020.146863"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.924173"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00658-07"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.8.2793\u20102798.2004"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11011\u2010021\u201000796\u20103"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12890\u2010019\u20100955\u2010y"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1590\/S0004-282X2007000700012"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-642-13443-2_9"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a020412"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24032852"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0288055"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1097\/WNP.0000000000000565"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.2174\/1389200217666160406115959"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-8-38"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.18683\/germs.2024.1428"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12028\u2010019\u201000894\u20102"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.3.1699"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23052717"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10072\u2010012\u20100939\u20107"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471\u20104159.2001.00621.x"},{"key":"e_1_2_8_65_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-017-2288-7"},{"key":"e_1_2_8_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.braindev.2007.05.005"},{"key":"e_1_2_8_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2010.03.025"},{"key":"e_1_2_8_68_1","doi-asserted-by":"publisher","DOI":"10.1177\/096805199500200105"},{"key":"e_1_2_8_69_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.13408"},{"key":"e_1_2_8_70_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2021.768108"},{"key":"e_1_2_8_71_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arcmed.2014.11.015"},{"key":"e_1_2_8_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.prp.2014.05.007"},{"key":"e_1_2_8_73_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00134\u2010004\u20102285\u20106"},{"key":"e_1_2_8_74_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.51832"},{"key":"e_1_2_8_75_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00134\u2010020\u201006050\u20101"},{"key":"e_1_2_8_76_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13054\u2010019\u20102378\u20109"},{"key":"e_1_2_8_77_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmicom.2024.100011"},{"key":"e_1_2_8_78_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.13607"},{"key":"e_1_2_8_79_1","doi-asserted-by":"publisher","DOI":"10.4103\/0253\u20107613.125192"},{"key":"e_1_2_8_80_1","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000032829"},{"key":"e_1_2_8_81_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12882\u2010017\u20100783\u20103"}],"container-title":["British Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bcp.70120","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T07:15:20Z","timestamp":1753773320000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1002\/bcp.70120"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,16]]},"references-count":80,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2025,8]]}},"alternative-id":["10.1002\/bcp.70120"],"URL":"https:\/\/doi.org\/10.1002\/bcp.70120","archive":["Portico"],"relation":{},"ISSN":["0306-5251","1365-2125"],"issn-type":[{"value":"0306-5251","type":"print"},{"value":"1365-2125","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,16]]}}}