Pharmacy Department, St. Vincent's Hospital, Sydney, NSW, 2010, Australia.
Department of Clinical Pharmacology and Toxicology, St. Vincent's Hospital, Sydney, NSW, 2010, Australia.
Int J Antimicrob Agents. 2023 Sep;62(3):106908. doi: 10.1016/j.ijantimicag.2023.106908. Epub 2023 Jun 28.
Tacrolimus is a CYP3A4 substrate with a narrow therapeutic index that requires dose adjustment when used with voriconazole, a recognized CYP3A4 inhibitor. Interactions involving flucloxacillin and tacrolimus or voriconazole individually have been shown to result in decreased concentrations of the latter two drugs. Tacrolimus concentrations have been reported to be unaffected by flucloxacillin when voriconazole is administered; however, this has not been extensively investigated.
Retrospective review of voriconazole and tacrolimus concentrations and subsequent dose adjustment following flucloxacillin administration.
Eight transplant recipients (five lung, two re-do lung, one heart) received concurrent flucloxacillin, voriconazole and tacrolimus. Voriconazole trough concentrations were measured before flucloxacillin initiation in three of eight patients and all trough concentrations were therapeutic. Following flucloxacillin initiation, all eight patients exhibited subtherapeutic concentrations of voriconazole (median concentration 0.15 mg/L [interquartile range (IQR) 0.10-0.28]). In five patients, voriconazole concentrations remained subtherapeutic despite dose increases, and treatment for two patients was changed to alternative antifungal agents. All eight patients required tacrolimus dose increases to maintain therapeutic concentrations after flucloxacillin initiation. Median total daily dose prior to flucloxacillin treatment was 3.5 mg [IQR 2.0-4.3] and this increased to 13.5 mg [IQR 9.5-20] (P=0.0026) during flucloxacillin treatment. When flucloxacillin was ceased, the median tacrolimus total daily dose reduced to 2.2 mg [IQR 1.9-4.7]. Supra-therapeutic tacrolimus concentrations were observed in seven patients after flucloxacillin discontinuation (median concentration 19.7 μg/L [IQR 17.9-28.0]).
A significant three-way interaction was shown between flucloxacillin, voriconazole and tacrolimus, resulting in subtherapeutic voriconazole concentrations, and requiring substantial tacrolimus dose increases. Administration of flucloxacillin to patients receiving voriconazole should be avoided. Tacrolimus concentrations should be closely monitored, and dosing adjusted during and after flucloxacillin administration.
他克莫司是一种 CYP3A4 底物，治疗指数较窄，与伏立康唑合用（一种公认的 CYP3A4 抑制剂）时需要调整剂量。已证明，涉及氟氯西林和他克莫司或伏立康唑的相互作用会导致后两者药物浓度降低。当给予伏立康唑时，曾报道氟氯西林不会影响他克莫司浓度；然而，这尚未得到广泛研究。
回顾性分析氟氯西林给药后伏立康唑和他克莫司浓度及后续剂量调整情况。
8 名（5 例肺移植、2 例再次肺移植、1 例心脏移植）接受者同时接受氟氯西林、伏立康唑和他克莫司治疗。8 例患者中有 3 例在开始氟氯西林治疗前测量了伏立康唑谷浓度，所有谷浓度均具有治疗作用。开始氟氯西林治疗后，8 例患者的伏立康唑浓度均低于治疗范围（中位数浓度为 0.15mg/L [四分位距（IQR）0.10-0.28]）。在 5 例患者中，尽管增加了剂量，但伏立康唑浓度仍低于治疗范围，因此对 2 例患者的治疗改为其他抗真菌药物。所有 8 例患者在开始氟氯西林治疗后均需要增加他克莫司剂量以维持治疗范围的浓度。氟氯西林治疗前的总日剂量中位数为 3.5mg [IQR 2.0-4.3]，氟氯西林治疗期间增加至 13.5mg [IQR 9.5-20]（P=0.0026）。当停止氟氯西林治疗时，他克莫司的总日剂量中位数减少至 2.2mg [IQR 1.9-4.7]。氟氯西林停止后，7 例患者的他克莫司浓度高于治疗范围（中位数浓度 19.7μg/L [IQR 17.9-28.0]）。
氟氯西林、伏立康唑和他克莫司之间存在显著的三向相互作用，导致伏立康唑浓度低于治疗范围，并需要大量增加他克莫司剂量。应避免给予接受伏立康唑治疗的患者氟氯西林。应密切监测他克莫司浓度，并在氟氯西林给药期间和之后调整剂量。
