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Abstract：
BACKGROUND: Intravenous fosfomycin (IVFOF) is gaining interest in severe infections. Its use may be limited by adverse events (AEs). Little experience exists on IVFOF therapeutic drug monitoring (TDM) in real-life setting.
METHODS: Retrospective study of patients receiving IVFOF for > 48 h at Policlinico Hospital (Milan, Italy) from 01/01/2019 to 01/01/2023. AEs associated to IVFOF graded CTCAE ≥ II were considered. Demographic and clinical risk factors for IVFOF-related AEs were analysed with simple and multivariable regression models. The determination of IVFOF TDM was made by a rapid ultraperformance liquid chromatography mass spectrometry method (LC-MS/MS) on plasma samples. The performance of TDM (trough levels (Cmin) in intermittent infusion, steady state levels (Css) in continuous infusion) in predicting AEs ≤ 5 days after its assessment was evaluated.
RESULTS: Two hundred and twenty-four patients were included. At IVFOF initiation, 81/224 (36.2%) patients were in ICU and 35/224 (15.7%) had septic shock. The most frequent infection site was the low respiratory tract (124/224, 55.4%). Ninety-five patients (42.4%) experienced ≥ 1AEs, with median time of 4.0 (2.0-7.0) days from IVFOF initiation. Hypernatremia was the most frequent AE (53/224, 23.7%). Therapy discontinuation due to AEs occurred in 38/224 (17.0%). ICU setting, low respiratory tract infections and septic shock resulted associated with AEs (RRadjusted 1.59 (95%CI:1.09-2.31), 1.46 (95%CI:1.03-2.07) and 1.73 (95%CI:1.27-2.37), respectively), while IVFOF daily dose did not. Of the 68 patients undergone IVFOF TDM, TDM values predicted overall AEs and hypernatremia with AUROC of 0.65 (95%CI:0.44-0.86) and 0.91 (95%CI:0.79-1.0) respectively for Cmin, 0.67 (95%CI:0.39-0.95) and 0.76 (95%CI:0.52-1.0) respectively for Css.
CONCLUSIONS: We provided real world data on the use of IVFOF-based regimens and associated AEs. IVFOF TDM deserves further research as it may represent a valid tool to predict AEs.
CONCLUSIONS: Real world data on intravenous fosfomycin for severe bacterial infections. AEs occurred in over 40% (therapy discontinuation in 17%) and were related to baseline clinical severity but not to fosfomycin dose. TDM showed promising results in predicting AEs.
METHODS: Retrospective study of patients receiving IVFOF for > 48 h at Policlinico Hospital (Milan, Italy) from 01/01/2019 to 01/01/2023. AEs associated to IVFOF graded CTCAE ≥ II were considered. Demographic and clinical risk factors for IVFOF-related AEs were analysed with simple and multivariable regression models. The determination of IVFOF TDM was made by a rapid ultraperformance liquid chromatography mass spectrometry method (LC-MS/MS) on plasma samples. The performance of TDM (trough levels (Cmin) in intermittent infusion, steady state levels (Css) in continuous infusion) in predicting AEs ≤ 5 days after its assessment was evaluated.
RESULTS: Two hundred and twenty-four patients were included. At IVFOF initiation, 81/224 (36.2%) patients were in ICU and 35/224 (15.7%) had septic shock. The most frequent infection site was the low respiratory tract (124/224, 55.4%). Ninety-five patients (42.4%) experienced ≥ 1AEs, with median time of 4.0 (2.0-7.0) days from IVFOF initiation. Hypernatremia was the most frequent AE (53/224, 23.7%). Therapy discontinuation due to AEs occurred in 38/224 (17.0%). ICU setting, low respiratory tract infections and septic shock resulted associated with AEs (RRadjusted 1.59 (95%CI:1.09-2.31), 1.46 (95%CI:1.03-2.07) and 1.73 (95%CI:1.27-2.37), respectively), while IVFOF daily dose did not. Of the 68 patients undergone IVFOF TDM, TDM values predicted overall AEs and hypernatremia with AUROC of 0.65 (95%CI:0.44-0.86) and 0.91 (95%CI:0.79-1.0) respectively for Cmin, 0.67 (95%CI:0.39-0.95) and 0.76 (95%CI:0.52-1.0) respectively for Css.
CONCLUSIONS: We provided real world data on the use of IVFOF-based regimens and associated AEs. IVFOF TDM deserves further research as it may represent a valid tool to predict AEs.
CONCLUSIONS: Real world data on intravenous fosfomycin for severe bacterial infections. AEs occurred in over 40% (therapy discontinuation in 17%) and were related to baseline clinical severity but not to fosfomycin dose. TDM showed promising results in predicting AEs.
摘要：
背景：静脉磷霉素（IVFOF）在严重感染中引起了人们的兴趣。其使用可能受到不良事件(AE)的限制。在现实生活中，IVFOF治疗药物监测（TDM）的经验很少。
方法：在Policlinico医院接受IVFOF>48小时的患者的回顾性研究（米兰，意大利）从2019年1月1日至2023年1月1日。考虑与IVFOF分级CTCAE≥II相关的AE。使用简单和多变量回归模型分析IVFOF相关AE的人口统计学和临床危险因素。采用快速超高效液相色谱-质谱(LC-MS/MS)法测定血浆样品中IVFOF-TDM的含量。间歇输液中TDM（波谷水平（Cmin）的表现，持续输注中的稳态水平（Css））在评估评估后5天预测AEs。
结果：纳入了二百二十四例患者。在IVFOF启动时，81/224（36.2％）患者在ICU，35/224（15.7％）患者发生感染性休克。最常见的感染部位是下呼吸道（124/224，55.4％）。95例患者（42.4%）经历≥1AE，从IVFOF开始的中位时间为4.0（2.0-7.0）天。高钠血症是最常见的AE（53/224，23.7%）。38/224（17.0%）发生因不良事件而停止治疗。ICU设置,下呼吸道感染和感染性休克与不良事件相关（RR调整1.59（95CI：1.09-2.31），1.46（95CI：1.03-2.07）和1.73（95CI：1.27-2.37），分别)，而IVFOF日剂量没有。在68例接受IVFOFTDM的患者中，TDM值预测总体AE和高钠血症，Cmin的AUROC分别为0.65（95CI：0.44-0.86）和0.91（95CI：0.79-1.0），Css分别为0.67（95CI：0.39-0.95）和0.76（95CI：0.52-1.0）。
结论：我们提供了关于使用基于IVFOF的方案和相关不良事件的真实世界数据。IVFOFTDM值得进一步研究，因为它可能是预测AE的有效工具。
结论：静脉注射磷霉素治疗严重细菌感染的真实世界数据。不良事件发生率超过40％（治疗中断17％），与基线临床严重程度有关，但与磷霉素剂量无关。TDM在预测AE方面显示出有希望的结果。
方法：在Policlinico医院接受IVFOF>48小时的患者的回顾性研究（米兰，意大利）从2019年1月1日至2023年1月1日。考虑与IVFOF分级CTCAE≥II相关的AE。使用简单和多变量回归模型分析IVFOF相关AE的人口统计学和临床危险因素。采用快速超高效液相色谱-质谱(LC-MS/MS)法测定血浆样品中IVFOF-TDM的含量。间歇输液中TDM（波谷水平（Cmin）的表现，持续输注中的稳态水平（Css））在评估评估后5天预测AEs。
结果：纳入了二百二十四例患者。在IVFOF启动时，81/224（36.2％）患者在ICU，35/224（15.7％）患者发生感染性休克。最常见的感染部位是下呼吸道（124/224，55.4％）。95例患者（42.4%）经历≥1AE，从IVFOF开始的中位时间为4.0（2.0-7.0）天。高钠血症是最常见的AE（53/224，23.7%）。38/224（17.0%）发生因不良事件而停止治疗。ICU设置,下呼吸道感染和感染性休克与不良事件相关（RR调整1.59（95CI：1.09-2.31），1.46（95CI：1.03-2.07）和1.73（95CI：1.27-2.37），分别)，而IVFOF日剂量没有。在68例接受IVFOFTDM的患者中，TDM值预测总体AE和高钠血症，Cmin的AUROC分别为0.65（95CI：0.44-0.86）和0.91（95CI：0.79-1.0），Css分别为0.67（95CI：0.39-0.95）和0.76（95CI：0.52-1.0）。
结论：我们提供了关于使用基于IVFOF的方案和相关不良事件的真实世界数据。IVFOFTDM值得进一步研究，因为它可能是预测AE的有效工具。
结论：静脉注射磷霉素治疗严重细菌感染的真实世界数据。不良事件发生率超过40％（治疗中断17％），与基线临床严重程度有关，但与磷霉素剂量无关。TDM在预测AE方面显示出有希望的结果。
