Hu Yan, Hegde Vishal, Johansen Daniel, Loftin Amanda H, Dworsky Erik, Zoller Stephen D, Park Howard Y, Hamad Christopher D, Nelson George E, Francis Kevin P, Scaduto Anthony, Bernthal Nicholas M
Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California Los Angeles, Santa Monica, California, United States of America.
Department of Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
PLoS One. 2017 Feb 28;12(2):e0173019. doi: 10.1371/journal.pone.0173019. eCollection 2017.
Management of spine implant infections (SII) are challenging. Explantation of infected spinal hardware can destabilize the spine, but retention can lead to cord compromise and biofilm formation, complicating management. While vancomycin monotherapy is commonly used, in vitro studies have shown reduced efficacy against biofilm compared to combination therapy with rifampin. Using an established in vivo mouse model of SII, we aim to evaluate whether combination therapy has increased efficacy compared to both vancomycin alone and infected controls.
An L-shaped, Kirschner-wire was transfixed into the L4 spinous process of 12-week-old C57BL/6 mice, and inoculated with bioluminescent Staphylococcus aureus. Mice were randomized into a vancomycin group, a combination group with vancomycin plus rifampin, or a control group receiving saline. Treatment began on post-operative day (POD) 7 and continued through POD 14. In vivo imaging was performed to monitor bioluminescence for 35 days. Colony-forming units (CFUs) were cultured on POD 35.
Bioluminescence peaked around POD 7 for all groups. The combination group had a 10-fold decrease in signal by POD 10. The vancomycin and control groups reached similar levels on POD 17 and 21, respectively. On POD 25 the combination group dropped below baseline, but rebounded to the same level as the other groups, demonstrating a biofilm-associated infection by POD 35. Quantification of CFUs on POD 35 confirmed an ongoing infection in all three groups.
Although both therapies were initially effective, they were not able to eliminate implant biofilm bacteria, resulting in a rebound infection after antibiotic cessation. This model shows, for the first time, why histologic-based, static assessments of antimicrobials can be misleading, and the importance of longitudinal tracking of infection. Future studies can use this model to test combinations of antibiotic therapies to see if they are more effective in eliminating biofilm prior to human trials.
脊柱植入物感染（SII）的管理具有挑战性。取出受感染的脊柱硬件可能会使脊柱不稳定，但保留硬件可能会导致脊髓受压和生物膜形成，从而使管理变得复杂。虽然万古霉素单一疗法常用，但体外研究表明，与利福平联合治疗相比，其对生物膜的疗效降低。使用已建立的SII体内小鼠模型，我们旨在评估联合治疗与单独使用万古霉素和感染对照组相比是否具有更高的疗效。
将一根L形克氏针固定到12周龄C57BL/6小鼠的L4棘突中，并接种生物发光金黄色葡萄球菌。小鼠被随机分为万古霉素组、万古霉素加利福平联合组或接受生理盐水的对照组。治疗在术后第7天（POD）开始，并持续到POD 14。进行体内成像以监测35天的生物发光。在POD 35培养菌落形成单位（CFU）。
所有组的生物发光在POD 7左右达到峰值。联合组在POD 10时信号下降了10倍。万古霉素组和对照组分别在POD 17和21达到相似水平。在POD 25时，联合组降至基线以下，但反弹至与其他组相同的水平，表明在POD 35时存在生物膜相关感染。POD 35时CFU的定量证实所有三组均存在持续感染。
虽然两种疗法最初都有效，但它们无法消除植入物生物膜细菌，导致抗生素停用后感染反弹。该模型首次表明了基于组织学的静态抗菌评估为何会产生误导，以及纵向跟踪感染的重要性。未来的研究可以使用该模型测试抗生素治疗组合，以查看它们在人体试验前消除生物膜方面是否更有效。
