Biomedical Advanced Research and Development Authority, Department of Health and Human Services, Washington, DC, USA.
Tunnell Government Services, Bethesda, Maryland, USA.
Antimicrob Agents Chemother. 2022 Oct 18;66(10):e0054622. doi: 10.1128/aac.00546-22. Epub 2022 Sep 26.
More evidence is needed to support recommendations for medical management of acute radiation syndrome (ARS) and associated infections resulting from a radiological/nuclear event. While current guidelines recommend the administration of antibiotics to chemotherapy patients with febrile neutropenia, the clinical benefit is unclear for acute radiation injury patients. A well-characterized nonhuman primate (NHP) model of hematopoietic ARS was developed that incorporates supportive care postirradiation. This model evaluated the efficacy of myeloid growth factors within 24 to 48 h after total body irradiation (TBI). However, in this model, NHPs continued to develop life-threatening bacterial infections, even when granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor was administered in combination with antibiotic monotherapy. In this study, we evaluated the efficacy of combination antibiotic therapies administered to NHPs following 7.4-Gy TBI to understand the occurrence of bacterial infection in NHPs with hematopoietic ARS. We compared enrofloxacin-linezolid, enrofloxacin-cefepime, and enrofloxacin-ertapenem to enrofloxacin monotherapy. The primary endpoint was 60-day postirradiation mortality, with secondary endpoints of overall survival time, incidence of bacterial infection, and bacteriologic culture with antimicrobial susceptibility testing. We observed that enrofloxacin-ertapenem significantly increased survival compared to enrofloxacin monotherapy. Bacteria isolated from nonsurviving macaques with systemic bacterial infections exhibited uniform resistance to enrofloxacin and variable resistance to beta-lactam antibiotics, linezolid, gentamicin, and azithromycin. Multidrug antibiotic resistance was observed in spp. and Escherichia coli. We conclude that antibiotic combination therapies appear to be more effective than monotherapy alone but acknowledge that more work is needed to identify an optimal antimicrobial therapy.
需要更多的证据来支持针对放射性/核事件引起的急性辐射综合征 (ARS) 和相关感染的医学管理建议。虽然目前的指南建议对发热性中性粒细胞减少症的化疗患者给予抗生素治疗，但对于急性辐射损伤患者，临床获益尚不清楚。已经开发出一种经过充分表征的非人类灵长类动物 (NHP) 造血性 ARS 模型，该模型纳入了放射后支持性护理。该模型评估了在全身照射 (TBI) 后 24 至 48 小时内给予骨髓生长因子的疗效。然而，在该模型中，即使给予粒细胞集落刺激因子或粒细胞-巨噬细胞集落刺激因子联合抗生素单药治疗，NHP 仍继续发生危及生命的细菌感染。在这项研究中，我们评估了在 7.4-Gy TBI 后给予 NHP 联合抗生素治疗的疗效，以了解造血性 ARS 的 NHP 中细菌感染的发生情况。我们比较了恩诺沙星-利奈唑胺、恩诺沙星-头孢吡肟和恩诺沙星-厄他培南与恩诺沙星单药治疗。主要终点是照射后 60 天的死亡率，次要终点是总生存时间、细菌感染发生率和细菌学培养与抗菌药物敏感性试验。我们观察到恩诺沙星-厄他培南与恩诺沙星单药治疗相比显著提高了生存率。从发生全身细菌感染且未存活的猕猴中分离出的细菌对恩诺沙星表现出一致的耐药性，对β-内酰胺类抗生素、利奈唑胺、庆大霉素和阿奇霉素表现出可变的耐药性。在 spp. 和大肠杆菌中观察到多药耐药性。我们得出结论，抗生素联合治疗似乎比单药治疗更有效，但也承认需要做更多的工作来确定最佳的抗菌治疗方法。
