Abstract
目的
研究不同因素对化脓性脊柱炎患者病原菌培养结果的影响,寻找临床可控因素,提高病原菌培养阳性率。
方法
回顾北京大学第一医院2011年1月至2017年7月期间收治的化脓性脊柱炎患者共40例,根据病原菌培养结果将患者分为培养阴性组和培养阳性组,分析临床可控因素和非可控因素对培养结果的影响。
结果
培养阳性的患者24例(60.00%),病原菌以革兰阳性球菌为主,共17例(68.00%)。对非可控因素分析显示,两组患者在年龄、性别、易感因素、脊柱外感染灶、视觉模拟评分(visual analogue score,VAS)、病程、脊柱受累部位、体温、全身炎症反应综合征发生率、白细胞计数、中性粒细胞百分比[(neutrophilic granulocyte)%,NE%]以及硬膜外脓肿的发生率上差异无统计学意义。培养阳性组患者的红细胞沉降率(erythrocyte sedimentation rate, ESR,Z=-2.269, P=0.023)、C-反应蛋白(C-reactive protein, CRP,Z=-2.058, P=0.040)、椎旁脓肿发生率[P a(Pearson Chi-square)=5.625,P=0.018]高于培养阴性组患者。对可控因素分析显示,培养前2周内应用抗生素(P=0.058, OR=4.030, 95%CI: 0.956~16.993)、组织匀浆(P=0.014, OR=0.171, 95%CI: 0.042~0.695)是影响培养结果的关键因素,不同术式对病原菌培养结果的影响差异无统计学意义。
结论
ESR、CRP水平高,合并椎旁脓肿的化脓性脊柱炎患者病原菌培养阳性率高。培养前2周内应用抗生素的患者病原菌培养阳性率低,组织匀浆能够显著提高患者病原菌培养阳性率,尤其适用于ESR、CRP水平低,无椎旁脓肿且培养前2周内应用抗生素的患者。
Keywords: 化脓性脊柱炎, 组织匀浆, 抗生素, 病原菌培养
Abstract
Objective
To investigate the effect of clinical factors on the pathogen culture results in the patients with pyogenic spondylitis, and to find out clinical controllable factors which could increase the positive rate of the pathogen culture.
Methods
A retrospective study reviewed 40 patients who were diagnosed with pyogenic spondylitis in Peking University First Hospital from January 2011 to July 2017. The patients were divided into two groups depending on the culture results, culture negative or culture positive. The influence of clinical uncontrollable factors [the patient’s age, gender, predisposing factors, infection site except spine, visual analogue score (VAS), course of disease, spinal segment, white blood cell (WBC), (neutrophilic granulocyte)% (NE%), the incidence of systemic inflammatory response syndrome (SIRS), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), the incidence of paravertebral abscess] and controllable factors (prior antibiotics exposure within 2 weeks, tissue homogenate, surgical approach) on pathogen culture results were analyzed.
Results
Of the 40 patients, 18 patients were female and 22 patients were male. Causative germ was identified in 24/40 patients (60.00%) and dominant by gram positive cocci (68.00%). For clinical uncontrollable factors, there was no significant difference between the two groups in the patient’s age, gender, predisposing factors, infection site except spine, VAS, course of disease, spinal segment, WBC, NE% and the incidence of SIRS. ESR [(94.38±6.91) mm/h, P=0.023)], CRP [(64.74±13.51) mg/L, P=0.040], and the incidence of paravertebral abscess (75%, P=0.018) in culture negative group were lower in contrast to culture positive group. For clinical controllable factors, prior antibiotics exposure within 2 weeks (P=0.058, OR=4.030, 95%CI: 0.956-16.993) and tissue homogenate (P=0.014, OR=0.171, 95%CI: 0.042-0.695) were significantly associated with the pathogen culture result. Surgical approach was not significantly associated with pathogen culture result.
Conclusion
Patients with high level of ESR, CRP, and paravertebral abscess, would have high positive rate of pathogenic culture. Prior antibiotics exposure was associated with lower positive pathogen culture rate. Culture with tissue homogenate was more likely to find the causative germ, especially for patients without paravertebral abscess who had low level of ESR, CRP and prior antibiotics exposure.
Keywords: Pyogenic spondylitis, Tissue homogenate, Antibiotics, Pathogen culture
化脓性脊柱炎主要由细菌血源性播撒导致,占全部骨骼肌肉系统感染总数的2%~4%。29%的化脓性脊柱炎患者在疾病进展过程中会出现神经系统症状[1,2],因此疾病早期应用敏感性抗菌药物至关重要。化脓性脊柱炎患者的血培养阳性率较低,大多数患者需要采取活检的方式明确病原菌。尽管如此,病原菌培养阳性率也仅为30%~60%[3,4,5,6,7,8,9]。对于培养阴性的患者,抗生素的选择只能凭借经验以及病原菌的分布情况,给这类患者的治疗带来了很大的困难。
对于骨与软组织感染病原菌培养结果的影响因素研究主要集中在假体周围感染领域[10,11,12],影响病原菌培养结果的因素众多,其中临床可控因素主要包括培养来源(关节液、超声裂解液、组织)以及培养前抗生素应用情况[13,14],但是上述可控因素对化脓性脊柱炎患者的培养结果产生何种影响,以往研究结果没有定论[15,16,17]。对于化脓性脊柱炎培养阴性的患者自身具有怎样的临床特征更是少有文献报道[18]。
本研究将不同培养结果的化脓性脊柱炎患者进行比较,分析临床可控因素以及非可控因素对化脓性脊柱炎患者病原菌培养结果的影响,探寻临床可控因素,以期提高化脓性脊柱炎患者病原菌培养的阳性率。
1. 资料与方法
1.1. 入组标准
回顾性分析北京大学第一医院骨科2011年1月至2017年7月收治的脊柱感染患者94例。诊断依照化脓性脊柱炎的诊断标准[7]:(1)患者脊柱或椎旁病灶内分离出致病菌;(2)患者存在连通脊柱或椎旁的窦道;(3)患者临床症状、体征、实验室以及影像学检查提示脊柱炎,血培养阳性或组织病理检查报告“急慢性炎性细胞浸润,并且无干酪样坏死和肉芽肿形成”。查阅94例患者的病历资料,排除结核、布氏杆菌、放线菌、真菌等特异性病原菌感染,确诊化脓性脊柱炎患者共40例,占患者总数的42.6%。根据治疗过程中病原菌培养结果,将患者分为培养阳性组和培养阴性组。
1.2. 治疗流程
对病原学证据不充分、无急诊手术指征、病变部位易于获取的患者进行穿刺活检,组织标本送病原菌培养和病理检查。穿刺后给予广谱抗生素抗感染治疗(糖肽类+碳青霉烯类),根据病原菌培养和药敏结果调整抗生素应用。对单纯应用抗生素控制不佳的患者进行开放清创手术,术中再次取组织送病原菌培养和病理检查,术后根据结果调整抗生素用药。患者仅进行穿刺或开放清创,记为1次培养;患者穿刺后需开放清创,记为2次培养。
1.3. 病原菌培养
手术室严格无菌条件下穿刺活检或开放手术获取病变组织标本。
匀浆组:选取组织标本放入经灭菌处理的一次性研磨器内,加入适量无菌生理盐水进行研磨,收集研磨后组织液体共20 mL,平均分成两份,加入需氧、厌氧瓶中送检。
非匀浆组:选取脓液稀释、收集病变部位灌洗液或无菌生理盐水洗涤破碎病变组织后加入需氧、厌氧瓶中送检,或以咽拭子蘸取病变组织、脓液后送检。
1.4. 评估指标
对比两组患者非可控因素的差异,非可控因素有:性别、年龄、感染高危因素(糖尿病、应用激素或免疫抑制剂)、脊柱外感染灶、病程、全身炎症反应综合征(systemic inflammatory response syndrome,SIRS)、白细胞(white blood cell, WBC)计数、中性粒细胞百分比[(neutrophilic granulocyte)%,NE%]、红细胞沉降率(erythrocyte sedimentation rate, ESR)、C-反应蛋白(C-reactive protein, CRP)、病变椎体节段、椎体病变数量、椎旁脓肿和椎管内脓肿。
分析不同的组织获取方式(穿刺活检、开放清创)、培养前2周内抗生素应用、组织处理方式(匀浆、非匀浆)等可控因素对培养结果的影响。
1.5. 统计学分析
数据结果用 SPSS 21.0统计软件进行分析,计量资料符合正态分布时采用均值±标准差表示,不符合正态分布时采用中位数(最小值、最大值)表示。两组数据比较前采用Shapiro-Wilk方法进行正态性检验,Levene检验方法进行方差齐性检验,满足条件时采用独立样本t检验,不满足条件时采用Mann whitney U秩和检验。本研究样本量≥40,分类变量采用Pearson卡方或连续校正的卡方检验,有序分类变量采用Mann whitney U秩和检验,采用Logistic回归分析可能影响培养结果的可控因素。P<0.05为差异有统计学意义(双侧检验)。
2. 结果
2.1. 非可控因素
40例患者中16例(40.00%)患者培养阴性,24例(60.00%)患者培养阳性:15例穿刺患者(包括1例术前血培养阳性),8例开放清创患者(包括4例术前血培养阳性),1例单纯术前血培养阳性、穿刺培养阴性患者。卡方分析显示,两组患者在年龄、性别、是否合并感染高危因素以及是否伴有脊柱外感染灶间的差异无统计学意义。两组患者病程、体温、SIRS等临床表现间的差异亦无统计学意义。实验室检查提示,培养阳性组患者的CRP(Z=-2.058, P=0.040)、ESR(Z=-2.269, P=0.023)高于培养阴性组患者,差异有统计学意义(P<0.05);而WBC、NE%在两组间差异无统计学意义。影像学检查提示,培养阳性患者椎旁脓肿[Pa(Pearson Chi-square)=5.625, P=0.018]的发生率高于培养阴性患者,差异有统计学意义;而病变椎体节段、数量,硬膜外脓肿的发生率间差异无统计学意义(表1)。
1.
化脓性脊柱炎患者的非可控因素
Uncontrollable factors of patients with pyogenic spondylitis
| Items | Culture - (n=16) | Culture + (n=24) | Statistic value | P |
| Quantitative data accord with normal distribution (age, WBC, NE%), expressed as (x±s). Quantitative data not accord with normal distribution (course of disease, CRP, ESR), expressed as median (min, max). Pa, Pearson Chi-square value; Pb, continuous correction value. DM, diabetes mellitus; SIRS, systemic inflammatory response syndrome; WBC, white blood cell; NE%, neutrophilic granulocyte%; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein. | ||||
| General | ||||
| Age/years | 55.81±3.95 | 59.13±2.22 | t=0.786 | 0.436 |
| Female, n | 8 | 10 | Pa=0.269 | 0.604 |
| Infection site except spine, n | 2 | 3 | Pb<0.001 | 1.000 |
| Predisposing factors (DM, oral immunosuppressive agents), n | 4 | 9 | Pa=0.684 | 0.408 |
| Clinical manifestation | ||||
| Course of disease/d | 60 (7, 270) | 50 (7, 240) | Z=-0.014 | 0.989 |
| Temperature, n | Z=-0.144 | 0.902 | ||
| <37.5 ℃ | 10 | 15 | ||
| 37.5-38.5 ℃ | 3 | 3 | ||
| >38.5 ℃ | 3 | 6 | ||
| SIRS, n | 2 | 9 | Pb=1.886 | 0.170 |
| Laboratory examination | ||||
| WBC/(×109/L) | 8.14±0.62 | 7.84±0.85 | t=-0.258 | 0.798 |
| NE% | 67.06±3.26 | 74.30±2.55 | t=1.765 | 0.086 |
| CRP/(mg/L) | 213.0 (93.1, 793.0) | 410.0 (59.8, 2 060.0) | Z=-2.058 | 0.040 |
| ESR/(mm/h) | 65.00 (12.00, 124.00) | 106.00 (36.00, 135.00) | Z=-2.269 | 0.023 |
| Imaging examination, n | ||||
| Spinal segment | Pa=0.269 | 0.182 | ||
| Cervical and thoracic | 8 | 7 | ||
| Lumbar | 8 | 17 | ||
| Multiple segment involvement | 2 | 5 | Pb=0.065 | 0.799 |
| Epidural abscess | 4 | 4 | Pb=0.059 | 0.809 |
| Paravertebral abscess | 6 | 18 | Pa=5.625 | 0.018 |
2.2. 培养阳性患者的病原菌分布和耐药情况
培养阳性患者的病原菌分布及耐药情况见表2,其中阳性球菌17例:金黄色葡萄球菌(Staphylococcus aureus)7例,其中耐甲氧西林菌株2例,沃氏葡萄球菌(Staphylococcus warneri)、无乳链球菌B群(Group B of Streptococcus lactis)各2例,链球菌(Streptococcus)、凝固酶阴性葡萄球菌(coagulase-negative Staphylococcus)、鹑鸡肠球菌(Enterococcus gallinarum)、山羊葡萄球菌(Staphylococcus caprae)各1例。阴性杆菌6例:大肠埃希菌(Escherichia coli)3例,均为产超广谱β内酰胺酶菌株,伤寒沙门菌(Salmonella typhia)、鲍曼不动杆菌(Acinetobacter baumannii)各1例,其中鲍曼不动杆菌耐药谱广,仅对复方新诺明敏感。厌氧菌2例:具核梭杆菌(Fusobacterium nucleatum)、藤黄微球菌(Micrococcus luteus)各1例。
2.
培养阳性患者的病原菌分布和耐药情况
Antibiotic susceptibilities of culture positive patients with pyogenic spondylitis
| Pathogen culture result (n) | Cipro | Moxi | Levo | Cef | R | Oxa | Vanco | Carba |
| -, not include. CN-S, coagulase negative Staphylococcus; S. aureus, Staphylococcus aureus; S. typhi, Salmonella typhia; E. coli, Escherichia coli; E. gallinarum, Enterococcus gallinarum; A. baumanii, Acinetobacter baumanii; S. caprae, Staphylococcus caprae; S. warneri, Staphylococcus warneri; S. agalactiae, Streptococcus agalactiae; P. aeruginosa, Pseudomonas aeruginosa; S. hominis, Staphylococcus hominis; F. nucleatum, Fusobacterium nucleatum; M. luteus, Micrococcus luteus; S. cohnii urealyticum, Staphylococcus cohnii urealyticum. Cipro, ciprofloxacin; Moxi, moxifloxacin; Levo, levofloxacin; Cef, ceftazidime; R, rifampin; Oxa, oxacillin; Vanco, vancomycin; Carba, carbapenem. | ||||||||
| CN-S (1) | - | - | - | - | - | - | - | - |
| S. warneri (2) | 0 | 0 | 0 | - | 0 | 1/2 | 0 | - |
| S. cohnii urealyticum (1) | 0 | 0 | 0 | - | 0 | 1/1 | 0 | - |
| S. caprae (1) | 0 | 0 | 0 | - | 0 | 0 | 0 | - |
| S. hominis (1) | 0 | 0 | 0 | - | 0 | 1/1 | 0 | - |
| S. aureus (7) | 1/7 | 0 | 0 | - | 0 | 2/7 | 0 | - |
| Streptococcus (1) | - | - | - | - | - | - | 0 | - |
| S. agalactiae B group (2) | - | 1/2 | 1/2 | - | - | - | 0 | - |
| E. gallinarum (1) | 0 | - | 0 | - | - | - | 0 | - |
| S. typhi (1) | 0 | - | 0 | 0 | - | - | - | - |
| E. coli (3) | 3/3 | - | 2/3 | 1/3 | - | - | - | 0 |
| P. aeruginosa (1) | 0 | - | 0 | 0 | - | - | - | 1/1 |
| A. Baumanii (1) | 1/1 | - | 1/1 | 1/1 | - | - | - | 1/1 |
| M. luteus (1) | - | - | - | - | - | - | - | - |
| F. nucleatum (1) | - | - | - | - | - | - | - | - |
2.3. 影响培养结果的可控因素分析
9例(22.50%)患者清创手术前未行穿刺活检,其中4例患者血培养阳性,2例病变位于颈椎,3例患者术前未诊断感染性疾病。9例患者中5例培养阳性,细菌培养阳性率55.56%。
31例(77.50%)患者进行了病灶穿刺活检,其中1例未送检培养,余下30例患者中15例培养阳性,培养阳性率50.00%。31例患者中16例需进一步采取手术清创治疗,16例患者中5例培养阳性。
对40例患者共计55次培养结果进行单因素、多因素Logistic回归分析显示,培养前2周内抗生素应用(P=0.058, OR=4.030, 95%CI: 0.956~16.993)、组织匀浆(P=0.014, OR=0.171, 95%CI: 0.042~0.695)是影响培养结果的关键因素(表3、4)。
3.
可能影响培养结果的可控因素
Controllable factors that may influence culture result
| Items | Culture - (n=30) | Culture + (n=25) | Statistic value | P |
| Pb, continuous correction value. | ||||
| Procedure | Pb=0.550 | 0.458 | ||
| Debridement | 15 (60.00%) | 10 (40.00%) | ||
| Aspiration | 15 (50.00%) | 15 (50.00%) | ||
| Prior antibiotics history (within 2 weeks) | Pb=1.872 | 0.171 | ||
| Yes | 21 (61.76%) | 13 (38.24%) | ||
| No | 9 (42.86%) | 12 (57.14%) | ||
| Tissue homogenate | Pb=3.669 | 0.055 | ||
| Yes | 7 (36.84%) | 12 (63.16%) | ||
| No | 23 (63.89%) | 13 (36.11%) | ||
4.
可控因素Logistic回归分析
Logistic regression analysis of association between culture result and controllable factors
| Items | Univariate analysis | Multivariate analysis | ||||
| P | OR | 95%CI | P | OR | 95%CI | |
| Aspiration | 0.459 | 0.667 | 0.228-1.950 | 0.717 | 0.790 | 0.220-2.834 |
| Prior antibiotics history (within 2 weeks) | 0.174 | 2.154 | 0.712-6.516 | 0.058 | 4.030 | 0.956-16.993 |
| Tissue homogenate | 0.059 | 0.330 | 0.104-1.045 | 0.014 | 0.171 | 0.042-0.695 |
3. 讨论
本研究40例患者中,培养阳性的患者和培养阴性的患者分别为24例和16例。培养阳性的患者中致病菌以革兰阳性球菌为主(68.00%),在革兰阳性球菌中以金黄色葡萄球菌多见,革兰阴性杆菌中以大肠埃希菌多见。本研究在致病菌的分布及耐药情况上与既往研究一致[19,20]。
不同培养结果的两组患者在年龄、性别、易感因素、脊柱外感染灶、视觉模拟评分(visual analogue score,VAS)、病程、脊柱受累部位、体温、SIRS发生率、WBC、NE%以及硬膜外脓肿发生率等临床特点上差异无统计学意义。培养阳性组患者ESR、CRP、椎旁脓肿的发生率高于培养阴性组患者,差异有统计学意义。Heyer等[6]的研究指出,血清CRP水平与病原菌培养结果呈正相关。Kim等[16]的研究显示伴有椎旁脓肿的患者培养阳性率更高。本研究进一步明确了较高水平的ESR、CRP、椎旁脓肿与病原菌培养阳性的相关性[6,16,18]。遗憾的是,临床医生仍无法对上述因素进行干预从而准确地获取致病菌信息。
本研究31例穿刺患者中,16例患者穿刺后因单纯抗生素治疗效果不佳而进一步实施开放清创手术,开放手术的实施在不同穿刺培养结果的两组患者间差异无统计学意义。Wang等[17]对41例化脓性脊柱炎患者的回顾性研究显示,病原菌培养阴性(OR=3.47, P=0.221)是患者单纯应用抗生素感染控制不佳的危险因素,增加了开放清创手术率。与研究结果不同可能与下列因素有关:首先本研究中培养阴性的患者常规应用糖肽类+碳青霉烯类强效、广谱抗生素,从培养阳性患者的致病菌耐药谱中可以看出,上述两种抗生素基本能够覆盖所有致病菌(1例广谱耐药鲍曼不动杆菌除外),而Wang等[17]的研究中抗生素应用为万古霉素或头孢唑林+庆大霉素,致病菌的耐药率较高。本研究中病原菌培养阴性的患者开放清创手术率与病原菌培养阳性的患者相近,广谱抗生素的长期应用会使患者出现耐药菌、二重感染、抗生素相关副反应的风险增加[21],虽然在本研究中并没有出现上述情况,但对于该风险仍不容忽视。
既往研究显示,化脓性脊柱炎患者的病原菌培养阳性率较低。Heyer等[6]对159例化脓性脊柱炎患者进行了CT引导下穿刺,致病菌培养阳性率为32%。Kim等[7]对134例化脓性脊柱炎患者进行了X线影像引导下穿刺,致病菌培养阳性率也仅为38.1%。如何提高化脓性脊柱炎患者病原菌培养的阳性率仍是临床研究的重点。
Hassoun等[5]的研究结果显示致病菌培养阳性率为52%,并提出培养前暂停抗生素应用能够提高培养阳性率。Sung等[4]的研究结果显示培养阳性率为30.5%,认为培养结果与培养前抗生素应用、培养取材部位相关。Kim等[16]和Wang等[17]的研究结果也显示,培养前应用抗生素会降低致病菌培养的阳性率。Marschall等[15]的研究报道致病菌培养阳性率为66%,并指出开放手术致病菌培养阳性率高于穿刺活检,认为致病菌培养阳性率与培养前是否应用抗生素无关。
Kim等[22]的研究对比了病变部位不同组织(骨组织、软组织)的培养结果,显示软组织是病原菌培养的最佳材料。唐旭等[13]的研究显示,在假体周围感染中,超声震荡能够显著增加病原菌培养阳性率。考虑到超声震荡过程中污染的风险较大,本研究将获取的软组织应用高压灭菌后的一次性研磨器进行研磨,将研磨后的组织匀浆送检培养,最大限度地降低污染的发生并提高病原菌培养阳性率。
本研究的55次致病菌培养阳性率为45.45%。培养前2周内应用抗生素的患者致病菌培养阳性率为38.24%,无抗生素接触史的患者致病菌培养阳性率为57.14%,而是否进行组织匀浆的致病菌培养阳性率分别为63.16%和36.11%。多因素回归分析显示,培养前2周内抗生素应用、组织匀浆是影响培养结果的关键因素,培养阳性率与手术方式无关。本研究显示,培养前2周内应用抗生素的化脓性脊柱炎患者病原菌培养阳性率低,而组织匀浆能够显著提高化脓性脊柱炎患者病原菌培养阳性率。组织匀浆培养的应用,更有利于明确化脓性脊柱炎患者的病原菌,为临床抗生素应用提供了依据。
本研究也存在一些不足,研究方法为回顾性研究,样本量有限,但本研究以病原菌培养结果为研究对象进行分析,明确了不同病原菌培养结果的化脓性脊柱炎患者的临床特点,并证实组织匀浆培养技术能够提高化脓性脊柱炎患者致病菌培养阳性率,特别是对于ESR、CRP水平低并且培养前2周内有抗生素应用的患者,使临床应用抗生素能够做到有的放矢。
综上所述,ESR、CRP水平高,出现椎旁脓肿的化脓性脊柱炎患者病原菌培养阳性率高,培养前2周内应用抗生素的化脓性脊柱炎患者病原菌培养阳性率低,组织匀浆能够显著提高化脓性脊柱炎患者病原菌培养阳性率,尤其适用于ESR、CRP水平低,无椎旁脓肿且培养前2周内应用抗生素的患者。
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