Markantonis Sophia L, Kostopanagiotou Georgia, Panidis Dimitris, Smirniotis Vassilios, Voros Dionisios
Laboratory of Biopharmaceutics and Pharmacokinetics, School of Pharmacy, University of Athens, Panepistimiopolis, Athens, Greece.
Clin Ther. 2004 Feb;26(2):271-81. doi: 10.1016/s0149-2918(04)90025-2.
The prophylactic administration of antimicrobial agents to surgical patients has become standard practice to minimize the risk for postsurgical infection. During surgery, factors such as renal clearance, fluid administration, and blood loss contribute to drug concentrations achieved in the blood and tissues. The aminoglycoside gentamicin was chosen to investigate these factors because it is used for standard antimicrobial prophylaxis in colorectal surgery.
The aim of this study was to investigate the effects of surgical blood loss and fluid volume replacement on gentamicin concentrations in serum and in 3 tissue types (subcutaneous fat, epiploic fat, and colonic wall) in patients undergoing colorectal surgery.
This uncontrolled, open-label study was conducted at the Aretaieion Hospital (Athens, Greece) between November 2002 and March 2003. Patients selected for this study were scheduled to undergo elective colorectal surgery of ? 2-hour duration with general and epidural anesthesia and to receive gentamicin as major antimicrobial prophylaxis. Blood and tissue samples were obtained concurrently at specific times throughout each procedure. The effect of intraoperative blood loss on gentamicin concentrations and its pharmacokinetic properties was determined.
Sixteen patients completed the study (11 men, 5 women; white race, 16 patients [100%]; mean [SD] age, 61 [3] years [range, 39-80 years]). Mean (SEM) serum gentamicin concentration was found to be insufficient; the maximum plasma drug concentration/minimum inhibitory concentration (MIC) ratio was <8:1 for pathogens commonly isolated in the surgical unit of the hospital (MIC: 1-4 microg/mL). The mean (SEM) concentration at first surgical incision was 7.83 (0.82) microg/mL and decreased to 2.60 (0.28) microg/mL at skin closure, resulting in borderline effectiveness even for susceptible gram-positive microorganisms (MIC approximately 1.0). Initially, mean (SEM) tissue gentamicin concentrations in subcutaneous fat, epiploic fat, and colonic wall were low (2.02 [0.34] microg/mL, 2.41 [0.42] microg/mL, and 1.93 [0.38] microg/mL, respectively) and decreased approximately 1.0 microg/mL ( approximately 50%) by skin closure. Statistically significant positive correlations were found between gentamicin concentrations in serum and tissues (P </= 0.03). A strong negative correlation was found between the intravenously administered fluids and gentamicin concentrations in serum and tissues (P </= 0.04).
In this study, the administration of a 2-mg/kg dose of gentamicin as antimicrobial prophylaxis during colorectal surgery associated with significant intraoperative blood loss and therefore requiring significant fluid replacement did not achieve concentrations of the drug above MICs for gram-negative microorganisms throughout the procedures in either serum or tissue samples.
对外科手术患者预防性使用抗菌药物已成为标准做法，以尽量降低术后感染风险。手术期间，诸如肾脏清除率、液体输注和失血等因素会影响血液和组织中达到的药物浓度。选择氨基糖苷类庆大霉素来研究这些因素，因为它用于结直肠手术的标准抗菌预防。
本研究的目的是调查结直肠手术患者术中失血和液体量补充对血清以及3种组织类型（皮下脂肪、网膜脂肪和结肠壁）中庆大霉素浓度的影响。
这项非对照、开放标签研究于2002年11月至2003年3月在阿雷泰厄翁医院（希腊雅典）进行。入选本研究的患者计划接受持续时间≥2小时的择期结直肠手术，采用全身麻醉和硬膜外麻醉，并接受庆大霉素作为主要抗菌预防药物。在每个手术过程中的特定时间同时采集血液和组织样本。确定术中失血对庆大霉素浓度及其药代动力学特性的影响。
16名患者完成了研究（11名男性，5名女性；白种人，16例患者[100%]；平均[标准差]年龄，61[3]岁[范围，39 - 80岁]）。发现平均（标准误）血清庆大霉素浓度不足；对于医院手术科室中常见分离病原体，最大血浆药物浓度/最低抑菌浓度（MIC）比值<8:1（MIC：1 - 4μg/mL）。首次手术切口时的平均（标准误）浓度为7.83（0.82）μg/mL，皮肤缝合时降至2.60（0.28）μg/mL，即使对于敏感革兰氏阳性微生物（MIC约为1.0），有效性也处于临界水平。最初，皮下脂肪、网膜脂肪和结肠壁中的平均（标准误）组织庆大霉素浓度较低（分别为2.02[0.34]μg/mL、2.41[0.42]μg/mL和1.93[0.38]μg/mL），到皮肤缝合时降低了约1.0μg/mL（约50%）。血清和组织中的庆大霉素浓度之间存在统计学显著正相关（P≤0.03）。静脉输注液体与血清和组织中的庆大霉素浓度之间存在强负相关（P≤0.04）。
在本研究中，在结直肠手术期间给予2mg/kg剂量的庆大霉素作为抗菌预防，该手术伴有大量术中失血且因此需要大量液体补充，在整个手术过程中，血清或组织样本中该药物的浓度均未达到革兰氏阴性微生物的MIC以上。
