{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T06:04:54Z","timestamp":1784009094311,"version":"3.55.0"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"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. Med."],"abstract":"<jats:p>Postoperative fever represents a common clinical challenge in orthopedics, and the differential diagnosis of its etiology directly influences anti-infective decision-making and patient outcomes. In the context of anti-infective therapy, \u201cdrug fever\u201d induced by antimicrobial agents themselves can easily be mistaken for uncontrolled or recurrent infection, leading to antibiotic overuse. This article reports the case of a 49-year-old male with a comminuted fracture of the right femur. Preoperatively, he presented with post-traumatic absorption fever. Postoperatively, due to intraoperative observation of fascial necrosis and a sharp rise in inflammatory markers, a high clinical suspicion of necrotizing fasciitis prompted the initiation of triple broad-spectrum antibiotic therapy (clindamycin + piperacillin-tazobactam + vancomycin). After initial infection control, a regular afternoon high-grade fever emerged in the second postoperative week, accompanied by a \u201cvancomycin infusion syndrome\u201d-like rash and agranulocytosis. Through systematic exclusion of infectious sources and a rigorous drug withdrawal trial, the final diagnosis was confirmed as \u201cantimicrobial-associated drug fever.\u201d This case comprehensively illustrates the three-stage dynamic evolution of perioperative fever: from \u201ctraumatic inflammation\u201d to \u201cbacterial infection\u201d and finally to \u201cdrug fever.\u201d It highlights that clinicians should maintain high vigilance during active anti-infective treatment for the sequential phenomenon whereby \u201cthe therapeutic agents themselves become a new source of fever after infection control,\u201d in order to avoid inappropriate prolongation of antibiotics due to misjudgment and to reinforce the principles of antimicrobial stewardship.<\/jats:p>","DOI":"10.3389\/fmed.2026.1830157","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T05:38:37Z","timestamp":1784007517000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["From suspected necrotizing fasciitis to diagnosed drug-induced fever: a diagnostic maze and reflections on anti-infection management in a case of postoperative fever after femoral fracture"],"prefix":"10.3389","volume":"13","author":[{"given":"Yaoxin","family":"Ao","sequence":"first","affiliation":[{"name":"Department of Orthopedics, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Duan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The University of Hong Kong-Shenzhen Hospital","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaomei","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanjiao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaxi","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sijie","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Can","family":"Qu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bixia","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinguo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1338247","DOI":"10.3389\/fmed.2024.1338247","article-title":"Drug-induced hypersensitivity syndrome related to piperacillin-tazobactam: a case report and review of the literature","volume":"11","author":"Shen","year":"2024","journal-title":"Front Med (Lausanne)"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1164187","DOI":"10.3389\/fimmu.2023.1164187","article-title":"The role of mtDAMPs in the trauma-induced systemic inflammatory response syndrome","volume":"14","author":"Ye","year":"2023","journal-title":"Front Immunol"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1038\/s41577-024-01027-3","article-title":"Damp sensing and sterile inflammation: intracellular, intercellular and inter-organ pathways","volume":"24","author":"Huang","year":"2024","journal-title":"Nat Rev Immunol"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1365015","DOI":"10.3389\/fimmu.2024.1365015","article-title":"Elevated levels of damage-associated molecular patterns Hmgb1 and S100a8\/A9 coupled with toll-like receptor-triggered monocyte activation are associated with inflammation in patients with myelofibrosis","volume":"15","author":"De Luca","year":"2024","journal-title":"Front Immunol"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1038\/s41419-024-06676-9","article-title":"Trauma-associated extracellular histones mediate inflammation via a MYD88-IRAK1-ERK signaling axis and induce lytic cell death in human adipocytes","volume":"15","author":"Roos","year":"2024","journal-title":"Cell Death Dis"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/j.jare.2025.07.047","article-title":"DAMP signaling networks: from receptors to diverse pathophysiological functions","volume":"83","author":"Chen","year":"2025","journal-title":"J Adv Res"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"1074207","DOI":"10.3389\/fimmu.2023.1074207","article-title":"Altered early immune response after fracture and traumatic brain injury","volume":"14","author":"Haffner-Luntzer","year":"2023","journal-title":"Front Immunol"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"e2409882","DOI":"10.1002\/advs.202409882","article-title":"Mild hyperthermia accelerates bone repair by dynamically regulating iNOS\/Arg1 balance in the early stage","volume":"12","author":"Zhao","year":"2025","journal-title":"Adv Sci (Weinh)"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"5989","DOI":"10.7150\/ijbs.116740","article-title":"Macrophage extracellular traps modulate the compensatory anti-inflammatory response syndrome through IL-33\/ST2 signaling in severe acute pancreatitis","volume":"21","author":"Zhou","year":"2025","journal-title":"Int J Biol Sci"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"e225","DOI":"10.1016\/j.chest.2021.10.026","article-title":"A 24-year-old man with dyspnea and a broken left femur","volume":"161","author":"Chieng","year":"2022","journal-title":"Chest"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1016\/j.actbio.2022.12.012","article-title":"Endowing biodegradable zinc implants with dual-function of antibacterial ability and osteogenic activity by micro-addition of Mg and Ag (\u2264 0.1 wt.%)","volume":"157","author":"Chen","year":"2023","journal-title":"Acta Biomater"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"e101","DOI":"10.1016\/j.chest.2023.04.039","article-title":"A 17-year-old male with hypoxemia after long-bone fracture","volume":"164","author":"Seo","year":"2023","journal-title":"Chest"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"e252875","DOI":"10.1001\/jamanetworkopen.2025.2875","article-title":"Increased utilization of overtime and agency nurses and patient safety","volume":"8","author":"Pittman","year":"2025","journal-title":"JAMA Netw Open"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1007\/s00604-025-06953-0","article-title":"Advances of immunosensors based on Noble metal composite materials for detecting procalcitonin","volume":"192","author":"Pei","year":"2025","journal-title":"Mikrochim Acta"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"1308","DOI":"10.1001\/jamasurg.2024.3365","article-title":"Necrotizing soft tissue infections: a review","volume":"159","author":"McDermott","year":"2024","journal-title":"JAMA Surg"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1016\/j.jaad.2023.02.073","article-title":"Drug-induced hypersensitivity syndrome\/drug reaction with eosinophilia and systemic symptoms. Part ii diagnosis and management","volume":"90","author":"Wei","year":"2024","journal-title":"J Am Acad Dermatol"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.1016\/j.jaip.2022.02.004","article-title":"Drug-induced hypersensitivity syndrome (DIHS)\/drug reaction with eosinophilia and systemic symptoms (DRESS): clinical features and pathogenesis","volume":"10","author":"Hama","year":"2022","journal-title":"J Allergy Clin Immunol Pract"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1016\/j.jaad.2023.02.072","article-title":"Drug-induced hypersensitivity syndrome\/drug reaction with eosinophilia and systemic symptoms. Part I. Epidemiology, pathogenesis, clinicopathological features, and prognosis","volume":"90","author":"Wei","year":"2024","journal-title":"J Am Acad Dermatol"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1016\/j.jcf.2023.12.003","article-title":"Lymphocyte transformation tests predict delayed-type allergy to piperacillin\/tazobactam in patients with cystic fibrosis","volume":"23","author":"Roehmel","year":"2024","journal-title":"J Cyst Fibros"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"1478545","DOI":"10.3389\/fimmu.2024.1478545","article-title":"A case report of severe drug-induced immune hemolytic anemia caused by piperacillin","volume":"15","author":"Zhao","year":"2024","journal-title":"Front Immunol"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1144","DOI":"10.1007\/s00134-022-06811-0","article-title":"Association of vancomycin plus piperacillin\u2013tazobactam with early changes in creatinine versus cystatin C in critically ill adults: a prospective cohort study","volume":"48","author":"Miano","year":"2022","journal-title":"Intensive Care Med"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1007\/s12016-021-08919-5","article-title":"Road less traveled: drug hypersensitivity to fluoroquinolones, vancomycin, tetracyclines, and macrolides","volume":"62","author":"Zhu","year":"2022","journal-title":"Clin Rev Allergy Immunol"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"3025","DOI":"10.1016\/j.jaip.2024.07.028","article-title":"A skin testing strategy for non-IgE-mediated reactions associated with vancomycin","volume":"12","author":"Lyu","year":"2024","journal-title":"J Allergy Clin Immunol Pract"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"znad438","DOI":"10.1093\/bjs\/znad438","article-title":"An observational cohort study on the effects of extended postoperative antibiotic prophylaxis on surgical-site infections in low- and middle-income countries","volume":"111","year":"2024","journal-title":"Br J Surg"},{"key":"ref25","first-page":"345","article-title":"Comparison of prophylactic intravenous antibiotic regimens after endoprosthetic reconstruction for lower extremity bone tumors: a randomized clinical trial","volume-title":"JAMA Oncol","author":"Ghert","year":"2022"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"e4507","DOI":"10.1093\/cid\/ciaa932","article-title":"Development of an electronic definition for de-escalation of antibiotics in hospitalized patients","volume":"73","author":"Moehring","year":"2021","journal-title":"Clin Infect Dis"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"826","DOI":"10.1093\/cid\/ciae253","article-title":"Preventing new gram-negative resistance through beta-lactam de-escalation in hospitalized patients with sepsis: a retrospective cohort study","volume":"79","author":"Teshome","year":"2024","journal-title":"Clin Infect Dis"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1186\/s13054-021-03787-z","article-title":"Timing of antibiotic therapy in the ICU","volume":"25","author":"Kollef","year":"2021","journal-title":"Crit Care"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1830157\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T05:38:38Z","timestamp":1784007518000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1830157\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,14]]},"references-count":28,"alternative-id":["10.3389\/fmed.2026.1830157"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2026.1830157","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,14]]},"article-number":"1830157"}}