Overlapping Science in Radiation and Sulfur Mustard Exposures of Skin and Lung: Consideration of Models, Mechanisms, Organ Systems, and Medical Countermeasures: Overlapping science in radiation and sulfur mustard injuries to lung and skin.

PURPOSE: To summarize presentations and discussions from the 2022 trans-agency workshop titled "Overlapping science in radiation and sulfur mustard (SM) exposures of skin and lung: Consideration of models, mechanisms, organ systems, and medical countermeasures." METHODS: Summary on topics includes: (1) an overview of the radiation and chemical countermeasure development programs and missions; (2) regulatory and industry perspectives for drugs and devices; 3) pathophysiology of skin and lung following radiation or SM exposure; 4) mechanisms of action/targets, biomarkers of injury; and 5) animal models that simulate anticipated clinical responses. RESULTS: There are striking similarities between injuries caused by radiation and SM exposures. Primary outcomes from both types of exposure include acute injuries, while late complications comprise chronic inflammation, oxidative stress, and vascular dysfunction, which can culminate in fibrosis in both skin and lung organ systems. This workshop brought together academic and industrial researchers, medical practitioners, US Government program officials, and regulators to discuss lung-, and skin- specific animal models and biomarkers, novel pathways of injury and recovery, and paths to licensure for products to address radiation or SM injuries. CONCLUSIONS: Regular communications between the radiological and chemical injury research communities can enhance the state-of-the-science, provide a unique perspective on novel therapeutic strategies, and improve overall US Government emergency preparedness.

Model for Evaluating Antimicrobial Therapy To Prevent Life-Threatening Bacterial Infections following Exposure to a Medically Significant Radiation Dose.

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 Enterococcus 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.