{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T07:25:34Z","timestamp":1792481134841,"version":"4.5.0"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T00:00:00Z","timestamp":1739404800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Although imipenem\/cilastatin (IMI\/CIL) has demonstrated favorable therapeutic efficacy against various infections, the incidence of potential adverse events (AEs) has escalated in parallel with its increased utilization and has been documented in clinical trials. However, a comprehensive understanding of real-world implications remains lacking.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>By conducting a comprehensive search in the FDA Adverse Event Reporting System (FAERS) database, AE reports associated with IMI\/CIL as the primary suspect (PS) were selected for analysis, spanning from the first quarter of 2004 to the fourth quarter of 2023. Utilizing disproportionality analysis techniques, potential signals of AE s were identified through reported odds ratio (ROR), proportional report ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayesian geometric mean (EBGM). The obtained results were systematically classified using Medical Dictionary for Regulatory Activities (MedDRA).<\/jats:p><\/jats:sec><jats:sec><jats:title>Result<\/jats:title><jats:p>From the first quarter of 2004 to the fourth quarter of 2023, a total of 2,574 reports documenting AEs associated with IMI\/CIL were obtained, with more than half (n = 1,517, 58.94%) involving individuals aged over 60\u00a0years old. Descriptive analysis was conducted based on age groups and time to onset, revealing that the majority of AEs occurred within 3\u00a0days. Adverse drug reactions caused by IMI\/CIL were classified into 24 system organ classes (SOCs) at the preferred term (PT) level. Furthermore, previously unreported and clinically significant AEs such as cerebral atrophy, and delirium were also identified at the PT level.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study offers a more comprehensive insight into the monitoring, supervision, and management of adverse drug reactions associated with IMI\/CIL. Clinicians should pay further attention to the implications of numerous AEs and their corresponding signal intensities, as well as unrecorded signals of severe AEs. This holds significant value in enhancing the clinical safety profile of IMI\/CIL.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1524159","type":"journal-article","created":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T07:09:18Z","timestamp":1739430558000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Real-world pharmacovigilance investigation of imipenem\/cilastatin: signal detection using the FDA Adverse Event Reporting System (FAERS) database"],"prefix":"10.3389","volume":"16","author":[{"given":"Peng","family":"Jia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusen","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shangyu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangliu","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixiang","family":"Lian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quanyou","family":"Lai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,2,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e0292123","DOI":"10.1371\/journal.pone.0292123","article-title":"Quantitative sonographic assessment of muscle thickness and fasciculations distribution is a sensitive tool for neuromuscular disorders","volume":"18","author":"Abraham","year":"2023","journal-title":"PLoS One"},{"key":"B2","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1080\/14740338.2017.1323867","article-title":"Empirical estimation of under-reporting in the U.S. Food and drug administration adverse event reporting system (FAERS)","volume":"16","author":"Alatawi","year":"2017","journal-title":"Expert Opin. Drug Saf."},{"key":"B3","doi-asserted-by":"publisher","first-page":"99","DOI":"10.2165\/00003495-199651010-00008","article-title":"Imipenem\/cilastatin: an update of its antibacterial activity, pharmacokinetics and therapeutic efficacy in the treatment of serious infections","volume":"51","author":"Balfour","year":"1996","journal-title":"Drugs"},{"key":"B4","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/s0924-8579(98)00094-6","article-title":"Carbapenems in clinical practice: a guide to their use in serious infection","volume":"11","author":"Bradley","year":"1999","journal-title":"Int. J. Antimicrob. Agents"},{"key":"B5","doi-asserted-by":"publisher","first-page":"e00047","DOI":"10.1128\/CMR.00047-19","article-title":"Epidemiology of \u03b2-lactamase-producing pathogens","volume":"33","author":"Bush","year":"2020","journal-title":"Clin. Microbiol. Rev."},{"key":"B6","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1016\/0002-9343(88)90071-x","article-title":"Factors predisposing to seizures in seriously ill infected patients receiving antibiotics: experience with imipenem\/cilastatin","volume":"84","author":"Calandra","year":"","journal-title":"Am. J. Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/0002-9343(85)90104-4","article-title":"Review of adverse experiences and tolerability in the first 2,516 patients treated with imipenem\/cilastatin","volume":"78","author":"Calandra","year":"1985","journal-title":"Am. J. Med."},{"key":"B8","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1093\/jac\/12.suppl_d.125","article-title":"Safety and tolerance comparison of imipenem-cilastatin to cephalothin and cefazolin","volume":"12","author":"Calandra","year":"1983","journal-title":"J. Antimicrob. Chemother."},{"key":"B9","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1002\/j.1552-4604.1988.tb05735.x","article-title":"The efficacy results and safety profile of imipenem\/cilastatin from the clinical research trials","volume":"28","author":"Calandra","year":"","journal-title":"J. Clin. Pharmacol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1093\/jac\/18.supplement_e.193","article-title":"The safety profile of imipenem\/cilastatin: worldwide clinical experience based on 3470 patients","volume":"18","author":"Calandra","year":"1986","journal-title":"J. Antimicrob. Chemother."},{"key":"B11","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.tox.2019.02.001","article-title":"Imipenem toxicity in male reproductive organs as a result of inflammatory microenvironment and oxidative stress in germinal cells","volume":"416","author":"Cherif","year":"2019","journal-title":"Toxicology"},{"key":"B12","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1007\/s10096-005-0021-y","article-title":"Neurotoxicity induced by beta-lactam antibiotics: from bench to bedside","volume":"24","author":"Chow","year":"2005","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"B13","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1128\/CMR.00037-09","article-title":"Three decades of beta-lactamase inhibitors","volume":"23","author":"Drawz","year":"2010","journal-title":"Clin. Microbiol. Rev."},{"key":"B14","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1007\/BF01967266","article-title":"Severe neutropenia in a patient treated with imipenem\/cilastatin","volume":"12","author":"Fari\u00f1as","year":"1993","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"B15","doi-asserted-by":"publisher","first-page":"594","DOI":"10.5414\/CP203811","article-title":"Safety profile of carbapenems: data mining of the FDA adverse events reporting system","volume":"59","author":"Ge","year":"2021","journal-title":"Int. J. Clin. Pharmacol. Ther."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1843","DOI":"10.1345\/aph.1L307","article-title":"Cephalosporin-induced neurotoxicity: clinical manifestations, potential pathogenic mechanisms, and the role of electroencephalographic monitoring","volume":"42","author":"Grill","year":"2008","journal-title":"Ann. Pharmacother."},{"key":"B17","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1111\/j.1365-2125.2011.03991.x","article-title":"Neurotoxic effects associated with antibiotic use: management considerations","volume":"72","author":"Grill","year":"2011","journal-title":"Br. J. Clin. Pharmacol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"k4369","DOI":"10.1136\/bmj.k4369","article-title":"Clostridium difficile associated disease","volume":"363","author":"Hassoun","year":"2018","journal-title":"BMJ"},{"key":"B19","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1111\/j.1528-1157.1983.tb04913.x","article-title":"Epileptogenic activity of cephalosporins in rats and their structure-activity relationship","volume":"24","author":"Kamei","year":"1983","journal-title":"Epilepsia"},{"key":"B20","doi-asserted-by":"publisher","first-page":"692","DOI":"10.1046\/j.1528-1157.2001.30600.x","article-title":"Visual sensitivity and epilepsy: a proposed terminology and classification for clinical and EEG phenomenology","volume":"42","author":"Kasteleijn-Nolst Trenit\u00e9","year":"2001","journal-title":"Epilepsia"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1590","DOI":"10.1046\/j.1528-1157.2001.34701.x","article-title":"Seizures in the critically ill: the role of imipenem","volume":"42","author":"Koppel","year":"2001","journal-title":"Epilepsia"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1605","DOI":"10.1093\/ajhp\/53.13.1605","article-title":"Seizures related to use of imipenem-cilastatin","volume":"53","author":"Lane","year":"1996","journal-title":"Am. J. Health Syst. Pharm."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1459","DOI":"10.1177\/106002809202601125","article-title":"Imipenem\/cilastatin-associated hiccups","volume":"26","author":"Lucena","year":"1992","journal-title":"Ann. Pharmacother."},{"key":"B24","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1093\/jac\/34.2.223","article-title":"Comparison of methodologies used in assessing the postantibiotic effect","volume":"34","author":"MacKenzie","year":"1994","journal-title":"J. Antimicrob. Chemother."},{"key":"B25","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1592\/phco.31.4.408","article-title":"Epileptogenic potential of carbapenem agents: mechanism of action, seizure rates, and clinical considerations","volume":"31","author":"Miller","year":"2011","journal-title":"Pharmacotherapy"},{"key":"B26","doi-asserted-by":"publisher","first-page":"87","DOI":"10.2165\/00002018-199615020-00001","article-title":"Neurotoxicity of carbapenem antibacterials","volume":"15","author":"Norrby","year":"1996","journal-title":"Drug Saf."},{"key":"B27","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1136\/jnnp.57.3.383","article-title":"Worsening of myasthenia gravis on treatment with imipenem\/cilastatin","volume":"57","author":"O'Riordan","year":"1994","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"B28","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1046\/j.1469-0691.2000.00107.x","article-title":"Recommendation for treatment of severe infections caused by Enterobacteriaceae producing extended-spectrum beta-lactamases (ESBLs)","volume":"6","author":"Paterson","year":"2000","journal-title":"Clin. Microbiol. Infect."},{"key":"B29","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1128\/CMR.18.4.657-686.2005","article-title":"Extended-spectrum beta-lactamases: a clinical update","volume":"18","author":"Paterson","year":"2005","journal-title":"Clin. Microbiol. Rev."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1319","DOI":"10.1016\/S1473-3099(18)30554-1","article-title":"Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial","volume":"18","author":"Portsmouth","year":"2018","journal-title":"Lancet Infect. Dis."},{"key":"B31","doi-asserted-by":"publisher","first-page":"358","DOI":"10.5414\/CP204215","article-title":"Imipenem cilastatin sodium-associated thrombocytopenia in an older patient: a case report and literature review","volume":"60","author":"Qiao","year":"2022","journal-title":"Int. J. Clin. Pharmacol. Ther."},{"key":"B32","doi-asserted-by":"publisher","first-page":"92","DOI":"10.7326\/0003-4819-101-1-92","article-title":"The neurotoxicity of antibacterial agents","volume":"101","author":"Snavely","year":"1984","journal-title":"Ann. Intern Med."},{"key":"B33","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1016\/j.biopha.2017.08.039","article-title":"A carbapenem antibiotic imipenem\/cilastatin induces an oxidative stress-status and gonadotoxic effects in \u00ab wistar \u00bb rats","volume":"95","author":"Tahri","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"B34","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.tox.2018.05.011","article-title":"Exposure to imipenem\/cilastatin causes nephrotoxicity and even urolithiasis in Wistar rats","author":"Tahri","year":"2018","journal-title":"Toxicology"},{"key":"B35","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1007\/s40801-021-00268-1","article-title":"Delirium associations with antibiotics: a pharmacovigilance study of the FDA adverse event reporting system (FAERS)","volume":"9","author":"Teng","year":"2022","journal-title":"Drugs Real World Outcomes"},{"key":"B36","doi-asserted-by":"publisher","first-page":"e4539","DOI":"10.1093\/cid\/ciaa803","article-title":"A randomized, double-blind, multicenter trial comparing efficacy and safety of imipenem\/cilastatin\/relebactam versus piperacillin\/tazobactam in adults with hospital-acquired or ventilator-associated bacterial pneumonia (RESTORE-IMI 2 study)","volume":"73","author":"Titov","year":"2021","journal-title":"Clin. Infect. Dis."},{"key":"B37","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1046\/j.1469-0691.2000.00082.x","article-title":"Meropenem versus imipenem\/cilastatin as empirical monotherapy for serious bacterial infections in the intensive care unit","volume":"6","author":"Verwaest","year":"2000","journal-title":"Clin. Microbiol. Infect."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1027","DOI":"10.2165\/00003495-200767070-00006","article-title":"Comparative review of the carbapenems","volume":"67","author":"Zhanel","year":"2007","journal-title":"Drugs"},{"key":"B39","doi-asserted-by":"publisher","first-page":"2195","DOI":"10.1007\/s15010-024-02248-3","article-title":"Safety evaluation of ceftazidime\/avibactam based on FAERS database","volume":"52","author":"Zhang","year":"2024","journal-title":"Infection"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1524159\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T07:09:22Z","timestamp":1739430562000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1524159\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,13]]},"references-count":39,"alternative-id":["10.3389\/fphar.2025.1524159"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1524159","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,13]]},"article-number":"1524159"}}