Table2_Antibiotic-Induced Neutropenia in Pediatric Patients: New Insights From Pharmacoepidemiological Analyses and a Systematic Review.docx

Aim: to characterize pediatric cases of antibiotic-associated neutropenia through a multidisciplinary approach, focusing on the temporal association between the wide spectrum of treatment options and the occurrence of this relatively uncommon but potentially clinically relevant adverse event.
Methods: we carried out a pharmacoepidemiological analysis based on the FDA Adverse Event Reporting System (FAERS) database, a retrospective chart review and a systematic review of the literature, focusing on the time to onset (TTO) of this side effect, in the pediatric clinical setting.
Results: A total of 281 antibiotic-related neutropenia events, involving 11 categories of antibiotics, were included in the time to onset analysis. The median TTO ranged from 4 to 60 days after the start of the therapy. A shorter median TTO was found from the retrospective chart review [16 patients: median days (25th-75th percentiles) = 4 (3–5)], compared to 15 (9–18) vs. 10 (6–18) for literature (224 patients) and FAERS (41 cases), respectively. The Anatomical Therapeutic Chemical classes, J01X, J01F, J01E and J04A, and the median TTOs retrieved from more than one source revealed high accordance (p > 0.05), with J01X causing neutropenia in less than a week and J01F/J01E/J04A in more than 10 days. Antibiotics were discontinued in nearly 34% of cases. In FDA Adverse Event Reporting System reports, half of the patients experiencing neutropenia were hospitalized.
Conclusion: Whereas antibiotic associated neutropenia is benign in the majority of cases, yet it should not be neglected as, even if rarely, it may put children at higher risk of clinical consequences. Clinicians’ awareness of antibiotic-associated neutropenia and its mode of presentation contributes to the continuous process of monitoring safety of antibiotics.

研究目的：采用多学科方法对儿科抗生素相关性中性粒细胞减少症病例进行特征分析，重点关注广谱治疗方案与该相对罕见但具有临床意义的不良事件发生之间的时间相关性。
研究方法：基于美国食品药品监督管理局不良事件报告系统（FDA Adverse Event Reporting System, FAERS）数据库开展药物流行病学分析，同时结合回顾性病历审查与系统文献综述，聚焦儿科临床场景下该不良反应的发病时间（time to onset, TTO）。
研究结果：本次发病时间分析共纳入281例抗生素相关性中性粒细胞减少事件，涉及11类抗生素。患者的发病时间中位数为治疗开始后4~60天。回顾性病历审查组的发病时间中位数更短[16例患者：中位数天数（第25~75百分位数）=4（3~5）]，而文献研究组（224例患者）与FAERS数据库组（41例患者）的发病时间中位数分别为15（9~18）天与10（6~18）天。通过多源数据验证的解剖治疗化学（Anatomical Therapeutic Chemical, ATC）分类J01X、J01F、J01E及J04A与发病时间中位数具有高度一致性（P>0.05）：J01X类药物所致中性粒细胞减少症发病时间不足1周，而J01F、J01E及J04A类药物所致病例的发病时间则超过10天。近34%的病例停用了抗生素。在FAERS报告中，发生中性粒细胞减少症的患者中有一半为住院患者。
研究结论：尽管多数抗生素相关性中性粒细胞减少症病例表现为良性病程，但仍不可忽视——即便罕见，该病症仍可能使儿童面临更高的临床不良结局风险。临床医师对该病及其临床表现的认知，有助于持续开展抗生素安全性监测工作。