Allababidi S, Shah J C
Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston 29425, USA.
Pharm Res. 1998 Feb;15(2):325-33. doi: 10.1023/a:1011939323560.
The study objective was to evaluate the efficacy and pharmacokinetics of cefazolin delivered locally as a glyceryl monostearate (GMS) based biocompatible implant for prevention of post-operative wound infection in Sprague Dawley rats subcutaneously inoculated with Staphylococcus aureus.
For the efficacy and pharmacokinetic studies, 18 rats were subcutaneously inoculated with 4.5 x 10(7) CFU of S. aureus on the dorsum (6 per rat), and randomly assigned into three group of 6 rats each: (1) the control group, in which rats did not receive antibiotics, (2) the intermittent i.m. treatment group, in which rats received i.m. injections of 10 mg/kg cefazolin every 4 hr (total of 180 mg/kg in 3 days), and (3) the implant treatment group, in which rats were implanted subcutaneously with four Cefazolin-GMS implants in the vicinity of the inoculations. The implants were designed to deliver 180 mg/kg cefazolin over a 3 day period. For efficacy evaluation, the rats were euthanized one week post-inoculation and abscess count, weight and size were determined.
Rats in the control group had developed 21 abscesses out of the 36 inoculations, indicating validity of the infection model. The local delivery of cefazolin resulted in complete eradication of the infection, since no abscesses formed in the rats in the implant group. In the IM treatment group, only one abscess was formed and no significant difference in efficacy between the two treatment groups was observed. The GMS implants sustained the release of cefazolin for a period of three days with only 3-fold fluctuations in plasma concentration (5.5-17.5 micrograms/ml). However, plasma concentrations after the intermittent IM administration of cefazolin fluctuated 110-fold between 44-0.4 micrograms/ml every 4 hr. The release rate of cefazolin from the implants was nearly zero order for the entire duration. Bioerosion of the implants was determined by examining the condition of the implants six weeks post-implantation. Two of the 12 implants had completely disappeared and the remaining implants were in a pasty form and had lost 20-80% of their weight. Absence of irritation or inflammation around the implants indicated biocompatibility of the GMS implants.
Implantable system that provided a prolonged delivery of cefazolin was found to be effective against S. aureus infection, and demonstrated suitable pharmacokinetics and biocompatibility with significant bioerosion.
本研究的目的是评估以硬脂酸甘油酯（GMS）为基础的生物相容性植入物局部递送头孢唑林预防皮下接种金黄色葡萄球菌的Sprague Dawley大鼠术后伤口感染的疗效和药代动力学。
为进行疗效和药代动力学研究，18只大鼠在背部皮下接种4.5×10⁷CFU金黄色葡萄球菌（每只大鼠接种6处），并随机分为三组，每组6只：（1）对照组，大鼠不接受抗生素治疗；（2）间歇性肌肉注射治疗组，大鼠每4小时肌肉注射10mg/kg头孢唑林（3天内总量为180mg/kg）；（3）植入物治疗组，大鼠在接种部位附近皮下植入4个头孢唑林-GMS植入物。这些植入物设计为在3天内递送180mg/kg头孢唑林。为评估疗效，接种一周后对大鼠实施安乐死，并确定脓肿数量、重量和大小。
对照组大鼠的36处接种中有21处形成脓肿，表明感染模型有效。头孢唑林的局部递送导致感染完全消除，因为植入物组的大鼠未形成脓肿。在肌肉注射治疗组中，仅形成1处脓肿，且未观察到两个治疗组在疗效上有显著差异。GMS植入物使头孢唑林持续释放3天，血浆浓度仅波动3倍（5.5 - 17.5微克/毫升）。然而，头孢唑林间歇性肌肉注射后的血浆浓度每4小时在44 - 0.4微克/毫升之间波动110倍。植入物中头孢唑林的释放速率在整个持续时间内几乎为零级。通过检查植入六周后植入物的状况来确定植入物的生物侵蚀情况。12个植入物中有2个已完全消失，其余植入物呈糊状，重量减轻了20 - 80%。植入物周围无刺激或炎症表明GMS植入物具有生物相容性。
发现可提供头孢唑林延长递送的植入系统对金黄色葡萄球菌感染有效，并显示出合适的药代动力学和生物相容性，伴有显著的生物侵蚀。
