The use of implantable gentamicin-impregnated collagen sponges did not reduce the sternal wound infection rate following cardiac surgery in a prospective, randomized, controlled trial of 1,502 patients who were at high risk of infection because of diabetes and/or obesity.
Dr. Elliott Bennett-Guerrero of Duke University in Durham, North Carolina, and his colleagues reported their findings Aug. 18 in JAMA.
The findings directly contradicted those of a 2005 Swedish study, which found that the sponges reduced surgical wound infections by 53%, and which served as strong preliminary data for the current trial (Ann. Thoracic. Surg. 2005;79:153-62).
The sponges are approved in 54 countries, and the current phase III study was designed to “confirm these promising data and support regulatory approval in the United States.” However, the overall wound infection rates at 90 days were statistically similar at 8.4% and 8.7%, respectively, in patients who received standard care plus surgical site implantation of two of the topical antibiotic sponges, and in patients who received standard care with no additional intervention, researchers found. There were 753 patients in the sponge group and 749 in the standard care group.
Like the overall wound infection rates, the superficial and deep sternal wound infection rates were also similar in the treatment and control groups, at 6.5% and 6.1%, and 1.9% and 2.5%, respectively. Additionally, no differences were seen between the treatment and control groups in regard to the rehospitalization rate for sternal wound infection (3.1% and 3.2%, respectively), or in ASEPSIS score (mean, 1.9 and. 2.0, respectively) the investigators found (JAMA 2010;304:755-62).
The ASEPSIS score is a measure of additional treatment, presence of serous discharge, erythema, purulent exudates, separation of the deep tissues, isolation of bacteria, and duration of inpatient stay. Points are assigned for each variable and the scale has a minimum score of 0, with no theoretical maximum, the investigators explained.
Patients in the single-blind study were enrolled at 48 U.S. centers between Dec. 21, 2007, and March 11, 2009. Those randomized to the treatment group underwent insertion of two sponges with a total gentamicin dose of 260 mg, which was the same dose used in the Swedish study. Both groups received standardized care with prophylactic systemic antibiotics and rigid sternal fixation, with the treatment group also undergoing implantation with the sponges.
The groups were balanced regarding baseline characteristics, including age, weight, diabetes, and smoking history, and also in regard to perioperative variables.
As for why the antibiotic sponges failed to reduce infection rates in this study as they did in the Swedish study, the investigators suggested that important quality control measures used in their study – but not in the Swedish study – might be to blame. They cited measures including on-site monitoring and source data verification, central adjudication of outcomes by an independent blinded committee, and the inclusion of a large number of hospitals (48 in the U.S. study, compared with 2 in the Swedish study).
The researchers also wrote that ethnic and regional differences, such as varying distribution of bacterial pathogens between countries, could also explain the differing outcomes. For example, no cases of methicillin-resistant Staphylococcus aureus occurred in the Swedish trial, but in the U.S. study 6.3% of patients had MRSA growth from sternal wound infection, which may not be sensitive to gentamicin.
“Thus, variations in the distribution of bacterial pathogens among countries could affect efficacy in a trial of infection prevention such as the present one,” they said, also noting that the findings underscore the importance of large validation trials, as “positive single-center trials are often not confirmed in larger multicenter trials.”
The U.S. study was sponsored by Innocoll Technologies Ltd., the maker of the gentamicin-collagen sponges, and Dr. Bennett-Guerrero reported that he is in discussions with Excited States LLC regarding a consulting agreement to advise on a clinical trial involving surgical wound infection prevention. Another author on the study, Dr. T. Bruce Ferguson Jr., reported receiving honoraria from Innocoll Technologies Ltd. for serving on a steering committee.
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一项纳入了1,502例因糖尿病和(或)肥胖而存在感染高风险的患者的前瞻性随机对照试验表明，植入式庆大霉素浸渍胶原海绵并不能降低心脏手术后胸骨伤口感染的发生率。
8月18日，美国北卡罗来纳州德汉姆杜克大学的Elliott Bennett-Guerrero博士及其同事在《美国医学会杂志》(JAMA)上报告了该试验的结果。
该试验结果直接推翻了2005年在瑞典开展的一项研究的结论，这项瑞典研究发现，这种海绵能使手术伤口的感染几率降低53%，目前这项试验也正是将此作为有力的初步数据(Ann. Thoracic. Surg. 2005;79:153-62)。
这种海绵已经在54个国家获准上市，目前开展的这项III期试验是为了“确认这些乐观的数据以支持其在美国获得监管机构的批准。”但研究者发现，术后第90天，接受了标准治疗加手术部位植入2片局部用抗生素海绵的患者的伤口感染总发生率为8.4%，而只接受了标准治疗没有附加其他干预措施的患者的伤口感染总发生率为8.7%，差异无统计学意义。海绵组和标准治疗组分别有753例和749例患者。
研究者发现，与伤口感染总发生率相似，治疗组与对照组的表皮和深部胸骨伤口感染的发生率也相近，分别为6.5%和 6.1%，以及1.9% 和2.5%。此外，在因胸骨伤口感染再次入院的发生率(分别为3.1%和3.2%)或ASEPSIS评分(平均评分分别为1.9分和2.0分)方面，治疗组与对照组之间亦无差异(JAMA 2010;304:755-62)。
研究者解释道，ASEPSIS评分是一种综合评价附加治疗、是否存在血清排出物、红斑、脓性渗出物、深部组织分离、细菌分离以及住院时间长短的指标。每一项参数都设定有一定的分值，量表的最低分为0，理论上没有限制最高分。
这项单盲试验于2007年12月21日~2009年3月11日在美国的48个医疗中心开展患者招募工作。被随机分配到治疗组的患者接受了庆大霉素总剂量为260 mg的2片海绵植入，这一剂量与瑞典研究所用剂量相同。两组患者均接受了标准治疗，即预防性使用全身性抗生素和坚固的胸骨固定，只是治疗组患者还接受了海绵植入。
两组患者在年龄、体重、糖尿病和吸烟史等基线特点以及术前参数方面是相似的。
对于为何在这项试验中抗生素海绵未能像瑞典研究所显示的那样降低感染的发生率，研究者认为这可能是因为这项试验采用了重要的质量控制措施，而那项瑞典研究并没有采取这类措施。研究者引述了其采用的部分措施，包括现场监测和源数据核实，由独立的盲性委员会对试验结果进行集中判定，并且所纳入的医院数量较多。
研究者还写道，种族和地区差异也可以解释为何这两项研究会得出不同的结果，比如各国之间致病菌的分布有所不同。举个例子，在瑞典试验中没有出现耐甲氧苯青霉素金黄色葡萄球菌(MRSA)感染的病例，但在这项美国试验中，6.3%的患者因胸骨伤口感染而出现了MRSA生长，这种致病菌可能对庆大霉素不敏感。
研究者说：“因此，各国之间在致病菌分布上的差异可能会影响到诸如这类感染预防试验的疗效。”研究者还指出，该试验结果强调了开展大规模确证试验的重要性，因为“单中心试验的阳性结果往往在大规模多中心试验中得不到证实。”
这项美国研究由庆大霉素胶原海绵的生产商Innocoll公司资助，Bennett-Guerrero博士声明目前正在与Excited States LLC公司商讨签署一份顾问协议的事宜，根据协议可能会对一项涉及手术伤口感染预防的临床试验提供建议。该试验的另一名作者T. Bruce Ferguson Jr.博士声明因担任指导委员会委员而接受了Innocoll公司提供的酬金。
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