椎间盘炎后不同类型抗生素在椎间盘内渗透情况与椎间盘弥散功能的相关性研究
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摘要
目的观察头孢唑林钠及克林霉素在感染椎间盘内的渗透情况,研究椎间盘内抗生素浓度与椎间盘弥散功能的相关性。方法取新西兰兔60只,制作椎间盘炎动物模型。在椎间隙感染后1、2、4、8、12周,每次随机取椎间盘炎模型兔12只,行连续动态增强磁共振成像(MRI)检测,测定椎间盘的弥散功能。将12只椎间盘炎模型兔随机分成2组,分别注射头孢唑林钠和克林霉素,每隔一个药物半衰期注射一次,共计给药5次,末次给药后间隔一个药物半衰期后抽取血样,并处死实验动物获取椎间盘髓核样本,采用高效液相-二级质谱联用方法测定血清和髓核药物浓度。同一时间点不同抗生素对感染及正常髓核组织的渗透率采用两样本t检验进行比较,椎间盘弥散功能比较、同一抗生素在不同时间点对感染及正常髓核组织渗透率的比较采用单因素方差分析和LSD法。采用直线相关检验分析正常及感染髓核中头孢唑林钠、克林霉素浓度与MRI增强后信号增强强度值之间的相关性。结果头孢唑林钠及克林霉素对感染椎间盘髓核组织的渗透率与对正常椎间盘髓核组织的渗透率比较,在椎间盘炎早期(感染后第1周、第2周、第4周)均增高,差异具有统计学意义[(头孢唑林钠:t=2.05,P=0.032;t=7.71,P <0.001;t=9.70,P <0.001),(克林霉素:t=2.68,P=0.015;t=4.25,P <0.001;t=7.42,P <0.001)],且均在感染第4周时达到最佳渗透率。在椎间盘炎中晚期﹙感染后第8周、第12周﹚,头孢唑林钠及克林霉素对感染椎间盘髓核组织的渗透率逐渐下降。头孢唑林钠对感染椎间盘髓核组织的渗透率与对正常椎间盘髓核组织的渗透率比较,第8周时差异无统计学意义(t=0.70,P=0.183),第12周时明显降低(t=-3.88,P <0.001)。克林霉素对感染椎间盘髓核组织的渗透率与对正常椎间盘髓核组织的渗透率比较,第8周(t=-2.57,P=0.010)和第12周时(t=-3.13,P=0.010)均明显降低,差异具有统计学意义。在感染后1、2、4、8、12周,克林霉素对感染椎间盘髓核组织的渗透率均明显高于头孢唑林钠的渗透率,差异均具有统计学意义(t=7.37,P <0.001;t=5.28,P <0.001;t=9.72,P <0.001;t=4.94,P <0.001;t=7.83,P <0.001)。正常(r=0.922)及感染(r=0.898)髓核组织中头孢唑林钠浓度与椎间盘弥散功能呈正相关关系;正常(r=0.923)及感染(r=0.896)髓核组织中克林霉素浓度与椎间盘弥散功能同样呈正相关关系。结论椎间盘炎发生后第4周头孢唑林钠及克林霉素对感染椎间盘髓核组织的渗透率最高,克林霉素的渗透率高于头孢唑林钠。应用连续动态增强MRI判断椎间盘对于抗生素的通透性可靠有效。
Objective To measure the intradiscal cefazolin sodium and clindamycin concentrations and explore the reliability of using endplate cartilage diffusion function to predict the intradiscal drug concentration in discitis. Methods Sixty New Zealand white rabbits were chosen to induce discitis. At 1, 2, 4, 8, and 12 weeks after surgery, 12 discitis rabbits were randomly chosen to undergo continuous dynamic contrast-enhanced MRI. The 12 rabbits were divided into two groups, and given a series of 5 halflife courses of intravenous injection of cefazolin sodium and clindamycin, respectively. Serum samples were obtained at one half-life of antibiotic after the last injection. Then, the rabbits were killed immediately and the nucleus pulposus was taken. Concentrations of the two antibiotics in serum and nucleus pulposus tissue were measured by high-pressure liquid chromatography. The permeability of different antibiotics to infected and normal nucleus pulposus at the same time points was compared by the two-samplet-test. The comparisons of intervertebral disc diffusion function and the permeability of the same antibiotic to infected and normal nucleus pulposus at different time points were analyzed by one-way analysis of variance and LSD method. Linear correlation test was used to analyze the correlation between cefazolin sodium and clindamycin concentrations in normal and infected nucleus pulposus and MRI-enhanced signal enhancement intensity values.Results The penetration of cefazolin and clindamycin into the infected disc significantly increased compared with that into the normal disc during the early infection period(1, 2, and 4 weeks)(cefazolin:t=2.05, P=0.032; t=7.71, P < 0.001; t=9.70, P < 0.001 and clindamycin: t=2.68, P=0.015; t=4.25,P < 0.001; t=7.42, P < 0.001), and achieved the best at 4 weeks of infection. Then, the penetration of cefazolin and clindamycin gradually decreased during the late period of infection(8 and 12 weeks). There was no signi?cant difference between the infected and normal discs in the penetration of cefazolin at 8 weeks(t=0.70, P=0.183); however, there was a signi?cant difference at 12 weeks(t=-3.88, P < 0.001). There was a signi?cant difference in the penetration of clindamycin into the infected and normal discs at 8(t=-2.57,P=0.010) and 12 weeks(t=-3.13, P=0.010). There were significant differences between the penetration of cefazolin and clindamycin into discs at 1, 2, 4, and 8 weeks post-infection(t=7.37, P < 0.001; t=5.28,P < 0.001; t=9.72, P < 0.001; t=4.94, P < 0.001; t=7.83, P < 0.001). A positive correlation existed between the penetration of cefazolin into the normal(r=0.922) and infected discs(r=0.898) and the diffuse function. A positive correlation also existed between the penetration of clindamycin into the normal(r=0.923)and infected discs(r=0.896) and the diffuse function. Conclusion The penetration of cefazolin and clindamycin into disc achieves the best at 4 weeks after infection. The permeability of clindamycin is superior to cefazolin and it is easier for clindamycin to achieve a higher concentration in the infected discs. The use of continuous dynamic enhanced MRI to predict the permeability of antibiotic is reliable and effective.
Objective To measure the intradiscal cefazolin sodium and clindamycin concentrations and explore the reliability of using endplate cartilage diffusion function to predict the intradiscal drug concentration in discitis. Methods Sixty New Zealand white rabbits were chosen to induce discitis. At 1, 2, 4, 8, and 12 weeks after surgery, 12 discitis rabbits were randomly chosen to undergo continuous dynamic contrast-enhanced MRI. The 12 rabbits were divided into two groups, and given a series of 5 halflife courses of intravenous injection of cefazolin sodium and clindamycin, respectively. Serum samples were obtained at one half-life of antibiotic after the last injection. Then, the rabbits were killed immediately and the nucleus pulposus was taken. Concentrations of the two antibiotics in serum and nucleus pulposus tissue were measured by high-pressure liquid chromatography. The permeability of different antibiotics to infected and normal nucleus pulposus at the same time points was compared by the two-samplet-test. The comparisons of intervertebral disc diffusion function and the permeability of the same antibiotic to infected and normal nucleus pulposus at different time points were analyzed by one-way analysis of variance and LSD method. Linear correlation test was used to analyze the correlation between cefazolin sodium and clindamycin concentrations in normal and infected nucleus pulposus and MRI-enhanced signal enhancement intensity values.Results The penetration of cefazolin and clindamycin into the infected disc significantly increased compared with that into the normal disc during the early infection period(1, 2, and 4 weeks)(cefazolin:t=2.05, P=0.032; t=7.71, P < 0.001; t=9.70, P < 0.001 and clindamycin: t=2.68, P=0.015; t=4.25,P < 0.001; t=7.42, P < 0.001), and achieved the best at 4 weeks of infection. Then, the penetration of cefazolin and clindamycin gradually decreased during the late period of infection(8 and 12 weeks). There was no signi?cant difference between the infected and normal discs in the penetration of cefazolin at 8 weeks(t=0.70, P=0.183); however, there was a signi?cant difference at 12 weeks(t=-3.88, P < 0.001). There was a signi?cant difference in the penetration of clindamycin into the infected and normal discs at 8(t=-2.57,P=0.010) and 12 weeks(t=-3.13, P=0.010). There were significant differences between the penetration of cefazolin and clindamycin into discs at 1, 2, 4, and 8 weeks post-infection(t=7.37, P < 0.001; t=5.28,P < 0.001; t=9.72, P < 0.001; t=4.94, P < 0.001; t=7.83, P < 0.001). A positive correlation existed between the penetration of cefazolin into the normal(r=0.922) and infected discs(r=0.898) and the diffuse function. A positive correlation also existed between the penetration of clindamycin into the normal(r=0.923)and infected discs(r=0.896) and the diffuse function. Conclusion The penetration of cefazolin and clindamycin into disc achieves the best at 4 weeks after infection. The permeability of clindamycin is superior to cefazolin and it is easier for clindamycin to achieve a higher concentration in the infected discs. The use of continuous dynamic enhanced MRI to predict the permeability of antibiotic is reliable and effective.
引文
1 Santhanam R,Lakshmi K.A retrospective analysis of the management of postoperative discitis:a single institutional experience[J].Asian Spine J,2015,9(4):559-564.
2 Aagaard T,Roed C,Larsen AR,et al.Long-term mortality after Staphylococcus aureus spondylodiscitis:a Danish nationwide population-based cohort study[J].J Infect,2014,69(3):252-258.
3 Shiban E,Janssen I,Wostrack M,et al.Spondylodiscitis by drugmultiresistant bacteria:a single-center experience of 25 cases[J].Spine J,2014,14(12):2826-2834.
4 Walters R,Rahmat R,Fraser R,et al.Preventing and treating discitis:cephazolin penetration in ovine lumbar intervertebral disc[J].Eur Spine J,2006,15(9):1397-1403.
5 Zhang L,Wang JC,Feng XM,et al.Antibiotic penetration into rabbit nucleus pulposus with discitis[J].Eur J Orthop Surg Traumatol,2014,24(4):453-458.
6 Curis E,Pestre V,Jullien V,et al.Pharmacokinetic variability of clindamycin and influence of rifampicin on clindamycin concentration in patients with bone and joint infections[J].Infection,2015,43(4):473-481.
7 Muftuler LT,Jarman JP,Yu HJ,et al.Association between intervertebral disc degeneration and endplate perfusion studied by DCE-MRI[J].Eur Spine J,2015,24(4):679-685.
8 Gullbrand SE,Peterson J,Mastropolo R,et al.Drug-induced changes to the vertebral endplate vasculature affect transport into the intervertebral disc in vivo[J].J Orthop Res,2014,32(12):1694-1700.
9 Zhu Q,Gao X,Li N,et al.Kinetics of charged antibiotic penetration into human intervertebral discs:a numerical study[J].J Biomech,2016,49(13):3079-3084.
10巫一鸣,卢善亮,许建国,等.抗生素对人颈椎椎间盘的渗透性研究[J].中国医药指南,2015,13(17):43-44.
11 Ibrahim MA,Haughton VM,Hyde JS.Effect of disk maturation on diffusion of low-molecular-weight gadolinium complexes:an experimental study in rabbits[J].AJNR Am J Neuroradiol,1995,16(6):1307-1311.
12张亮,王静成,冯新民,等.椎间隙感染后椎间盘组织及生化成分改变与椎间盘弥散功能的相关研究[J/CD].中华临床医师杂志(电子版),2014,8(19):3488-3494.
2 Aagaard T,Roed C,Larsen AR,et al.Long-term mortality after Staphylococcus aureus spondylodiscitis:a Danish nationwide population-based cohort study[J].J Infect,2014,69(3):252-258.
3 Shiban E,Janssen I,Wostrack M,et al.Spondylodiscitis by drugmultiresistant bacteria:a single-center experience of 25 cases[J].Spine J,2014,14(12):2826-2834.
4 Walters R,Rahmat R,Fraser R,et al.Preventing and treating discitis:cephazolin penetration in ovine lumbar intervertebral disc[J].Eur Spine J,2006,15(9):1397-1403.
5 Zhang L,Wang JC,Feng XM,et al.Antibiotic penetration into rabbit nucleus pulposus with discitis[J].Eur J Orthop Surg Traumatol,2014,24(4):453-458.
6 Curis E,Pestre V,Jullien V,et al.Pharmacokinetic variability of clindamycin and influence of rifampicin on clindamycin concentration in patients with bone and joint infections[J].Infection,2015,43(4):473-481.
7 Muftuler LT,Jarman JP,Yu HJ,et al.Association between intervertebral disc degeneration and endplate perfusion studied by DCE-MRI[J].Eur Spine J,2015,24(4):679-685.
8 Gullbrand SE,Peterson J,Mastropolo R,et al.Drug-induced changes to the vertebral endplate vasculature affect transport into the intervertebral disc in vivo[J].J Orthop Res,2014,32(12):1694-1700.
9 Zhu Q,Gao X,Li N,et al.Kinetics of charged antibiotic penetration into human intervertebral discs:a numerical study[J].J Biomech,2016,49(13):3079-3084.
10巫一鸣,卢善亮,许建国,等.抗生素对人颈椎椎间盘的渗透性研究[J].中国医药指南,2015,13(17):43-44.
11 Ibrahim MA,Haughton VM,Hyde JS.Effect of disk maturation on diffusion of low-molecular-weight gadolinium complexes:an experimental study in rabbits[J].AJNR Am J Neuroradiol,1995,16(6):1307-1311.
12张亮,王静成,冯新民,等.椎间隙感染后椎间盘组织及生化成分改变与椎间盘弥散功能的相关研究[J/CD].中华临床医师杂志(电子版),2014,8(19):3488-3494.