恶性梗阻性黄疸继发胆道感染病原学研究及多因素分析
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摘要
目的：分析恶性梗阻性黄疸(MOJ)继发胆系感染发生率,菌种分布构成,致病菌特点,筛选经皮穿刺胆道引流术(PTCD)治疗MOJ围手术期继发胆道感染的高危因素,探讨针对MOJ继发胆道感染的抗菌药物使用策略。
方法：选择2003年8月至2010年9月应用PTCD治疗的694例MOJ患者,其中男485例,女209例,年龄38岁-78岁,中位年龄62岁。术前血清总胆红素平均值(456.2±103.7)umol/L,黄疸病史9-32天。全部病例均经实验室、病理、影像学检查明确诊断为恶性肿瘤。其中胆管细胞癌22,9%例(159/694),胰腺癌18.9%(131/694),肝细胞肝癌16.9%(117/694),胃癌9.9%(69/694),胆囊癌7.1%(49/694),其他转移所致24.4%(169/694)。PTCD术中分别取胆汁10ml送检,应用BIOMERIUX公司VITEK2-COMPACT白动分析仪进行细菌鉴定及药敏试验。所有恶性梗阻性黄疸患者PTCD术前行血常规、肝功能、血凝常规、Treg (CD4+CD25+细胞)检查。采集患者性别、年龄(<65岁、≥65岁)、梗阻时间(<2周、≥2周)、原发肿瘤种类(胆管癌、胰腺癌、肝细胞肝癌、其他肿瘤)、梗阻部位(分为高位梗阻、低位梗阻)、引流方式(外引流、内外引流)、肿瘤分期(Ⅰ/Ⅱ期、Ⅲ/Ⅳ期)、血红蛋白(≥90g/L,<90g/L)、患者外周血单核细胞表型Treg (≥15%.<15%)、总胆红素(<300umol/L、≥300umol/L)直接胆红素(<200umol/L、≥200umol/L)、白蛋白(<30g/L、≥30g/L)、Child-Pugh评分(<11分,≥11分)、胆汁细菌培养结果等为研究参数。应用Pearson Chi-Square进行单因素分析,筛选出有统计学意义的因素后,再采用Logistic回归分析进行多因素分析。
结果：694例患者中298例胆汁培养阳性,古全组42.9%(298/694)。共分离出微生物342株。在同一患者胆汁标本培养细菌2株以上者32例,占全组10.7%(32/298)。根据临床症状、血常规检查结果,本组患者继发胆道感染者共156例,占本组22.5%(156/694)。鉴定微生物57种。分离出微生物342株中,革兰氏阳性菌占50.9%(174/342),革兰氏阴性菌占41.5%(142/342)。真菌5种,古本组7.6%(26/342)。本组共检出产超广谱β内酰胺酶(ESBLs)28株,产β内酰胺酶阳性48株,产酶G+菌构成比为27.6%(48/174),产酶G-菌构成比为19.7%(28/142),产酶大肠埃希菌构成比为61.8%(21/34)。本组恶性梗阻性黄疸胆汁培养结果有如下特点：(1)细菌种属数量多。(2)革兰氏阳性菌多于革兰氏阴性菌。(3)同一标本中有多种细菌共存,32例胆汁标本培养细菌2株以上,占10.7%(32/298)。(4)细菌产酶比例高,22.2%(76/342)为产酶细菌。对研究因素进行单因素分析,设定p<0.05有统计学意义,筛选出与胆道感染相关的因素有年龄≥65岁(χ2=4.621,p=0.032)、低位梗阻(χ2=17.450,p<0.001)、内外引流(χ2=14.452,p<0.001)、Ⅲ/Ⅳ期肿瘤(χ2=4.741,p=0.029)、血红蛋白<90g/L(χ2=3.914,p=0.048),肝功能Child-Pugh评分≥11分(χ2=5.491,p=0.019),患者外周血单核细胞表型Treg≥15%(x2=5.015, p=0.025),白蛋白<30g/L(χ2=4.776,p=0.029),胆汁细菌培养阳性(χ2=65.381,p<0.001)是PTCD围手术期继发胆道感染的高危因素。Logistic回归模型中多因素变量分析结果显示内外引流、肝功能Child-Pugh评分≥11分、胆汁细菌培养阳性结果是PTCD围手术期继发胆道感染的独立危险因素。
结论：MOJ继发胆道感染的胆汁细菌培养结果与良性梗阻性黄疸(BOJ)不同,主要特点是细菌种属数量较多；革兰氏阳性菌多于革兰氏阴性菌；同一标本中有多种细菌共存；细菌产酶比例高。MOJ胆汁细菌培养与药敏试验结果提示MOJ抗感染治疗具有一定特殊性、复杂性、难治性。内外引流、肝功能Child-Pugh评分≥11分、胆汁细菌培养阳性结果是PTCD围手术期继发胆道感染的独立危险因素。PTCD是采集MOJ胆汁标本的适宜方法。应该根据相关危险因素,制定完善PTCD围手术期胆道感染的预防与治疗策略。MOJ继发感染抗菌药物使用策略应有别于BOJ。
Objective:A retrospective one-center study was conducted to assess the information of bile culture and susceptibility testing special for malignant biliary obstruction and to get the risk factors of biliary system infection after percutaneous transhepatic cholangial drainage (PTCD) in malignant obstructive jaundice (MOJ) patients.
Methods:From August2003to September2010,694patients with malignant biliary obstruction received percutaneous transhepatic cholangial drainage (PTCD). Bile specimens were collected during the procedure of PTCD. Collect the information of gender, age, obstruction time,type of primartumor,site of obstruction, drainage style, tumor stage, hemoglobin, phenotype of peripheral blood mononuclear cell (Treg), bilirubin total, direct bilirubin, albumin, Child-Pugh score, and results of bile culture for Logistic multiplicity.
Results:There are694patients with malignant biliary obstruction in the study. There were485males and209females in the study with an age range of38-78years (mean62). There was no growth on bile culture in57.1%patients (396/694).42.9%patients had a positive bile culture (298/694) and342strains of microorganism were identified. There were156patients(22.3%,156/694) diagnosed by biliary infection.Gram-positive bacteria account for50.9%(174/342) and Gram-negative bacteria account for41.5%(142/342). No anaerobes were cultured in this research. The most frequent microorganisms were Enterococcus faecalis (12.0%,41/342), Escherichia coli (9.9%,34/342), Klebsiella pneumoniae (8.2%,28/342), Staphylococcus epidermidis (5.6%,19/342), Enterococcus (5.3%,18/342) and Enterobacter cloacae (4.7%,16/342). The rate of beta-lactamase producing Gram-positive bacteria was27.6%(48/174) and the rate of Gram-negative bacteria was19.7%(28/142). The rate of enzyme-producing Escherichia coli was61.8%(21/34). The risk factor of biliary system infection after PTCD include age (x2=4.621,p=0.032)、site of obstruction (x2=17.450,p<0.001)、drainage style (x2=14.452,p<0.001)、tumor stage (x2=4.741,p=0.029)、hemoglobin (x2=3.914 p=0.048), Child-Pugh score (x2=5.491,p=0.019), albumin<30g/L(x2=4.776,p=0.029), phenotype of peripheral blood mononuclear cell (Treg)(x2=5.015,p=0.025), results of bile culture(x2=65.381, p<0.001).And results of Logistic multiplicity is the risk factors were drainage style, Child-Pugh score and results of bile culture.
Conclusions:Our findings suggest the bile cultures in malignant biliary obstruction are different from those in Tokyo Guidelines and benign biliary obstruction researches, which indicate antibacterial therapy should be different. The risk factor of biliary system infection after PTCD include age, site of obstruction, drainage style, tumor stage,hemoglobin,Child-Pugh score, phenotype of peripheral blood mononuclear cell (Treg) and results of bile culture. And drainage style, Child-Pugh score and results of bile culture are independent risk factors. Knowledge of the antimicrobial susceptibility data could inform better use of antibiotics for empiric therapy for biliary infection with malignant biliary obstruction.
方法：选择2003年8月至2010年9月应用PTCD治疗的694例MOJ患者,其中男485例,女209例,年龄38岁-78岁,中位年龄62岁。术前血清总胆红素平均值(456.2±103.7)umol/L,黄疸病史9-32天。全部病例均经实验室、病理、影像学检查明确诊断为恶性肿瘤。其中胆管细胞癌22,9%例(159/694),胰腺癌18.9%(131/694),肝细胞肝癌16.9%(117/694),胃癌9.9%(69/694),胆囊癌7.1%(49/694),其他转移所致24.4%(169/694)。PTCD术中分别取胆汁10ml送检,应用BIOMERIUX公司VITEK2-COMPACT白动分析仪进行细菌鉴定及药敏试验。所有恶性梗阻性黄疸患者PTCD术前行血常规、肝功能、血凝常规、Treg (CD4+CD25+细胞)检查。采集患者性别、年龄(<65岁、≥65岁)、梗阻时间(<2周、≥2周)、原发肿瘤种类(胆管癌、胰腺癌、肝细胞肝癌、其他肿瘤)、梗阻部位(分为高位梗阻、低位梗阻)、引流方式(外引流、内外引流)、肿瘤分期(Ⅰ/Ⅱ期、Ⅲ/Ⅳ期)、血红蛋白(≥90g/L,<90g/L)、患者外周血单核细胞表型Treg (≥15%.<15%)、总胆红素(<300umol/L、≥300umol/L)直接胆红素(<200umol/L、≥200umol/L)、白蛋白(<30g/L、≥30g/L)、Child-Pugh评分(<11分,≥11分)、胆汁细菌培养结果等为研究参数。应用Pearson Chi-Square进行单因素分析,筛选出有统计学意义的因素后,再采用Logistic回归分析进行多因素分析。
结果：694例患者中298例胆汁培养阳性,古全组42.9%(298/694)。共分离出微生物342株。在同一患者胆汁标本培养细菌2株以上者32例,占全组10.7%(32/298)。根据临床症状、血常规检查结果,本组患者继发胆道感染者共156例,占本组22.5%(156/694)。鉴定微生物57种。分离出微生物342株中,革兰氏阳性菌占50.9%(174/342),革兰氏阴性菌占41.5%(142/342)。真菌5种,古本组7.6%(26/342)。本组共检出产超广谱β内酰胺酶(ESBLs)28株,产β内酰胺酶阳性48株,产酶G+菌构成比为27.6%(48/174),产酶G-菌构成比为19.7%(28/142),产酶大肠埃希菌构成比为61.8%(21/34)。本组恶性梗阻性黄疸胆汁培养结果有如下特点：(1)细菌种属数量多。(2)革兰氏阳性菌多于革兰氏阴性菌。(3)同一标本中有多种细菌共存,32例胆汁标本培养细菌2株以上,占10.7%(32/298)。(4)细菌产酶比例高,22.2%(76/342)为产酶细菌。对研究因素进行单因素分析,设定p<0.05有统计学意义,筛选出与胆道感染相关的因素有年龄≥65岁(χ2=4.621,p=0.032)、低位梗阻(χ2=17.450,p<0.001)、内外引流(χ2=14.452,p<0.001)、Ⅲ/Ⅳ期肿瘤(χ2=4.741,p=0.029)、血红蛋白<90g/L(χ2=3.914,p=0.048),肝功能Child-Pugh评分≥11分(χ2=5.491,p=0.019),患者外周血单核细胞表型Treg≥15%(x2=5.015, p=0.025),白蛋白<30g/L(χ2=4.776,p=0.029),胆汁细菌培养阳性(χ2=65.381,p<0.001)是PTCD围手术期继发胆道感染的高危因素。Logistic回归模型中多因素变量分析结果显示内外引流、肝功能Child-Pugh评分≥11分、胆汁细菌培养阳性结果是PTCD围手术期继发胆道感染的独立危险因素。
结论：MOJ继发胆道感染的胆汁细菌培养结果与良性梗阻性黄疸(BOJ)不同,主要特点是细菌种属数量较多；革兰氏阳性菌多于革兰氏阴性菌；同一标本中有多种细菌共存；细菌产酶比例高。MOJ胆汁细菌培养与药敏试验结果提示MOJ抗感染治疗具有一定特殊性、复杂性、难治性。内外引流、肝功能Child-Pugh评分≥11分、胆汁细菌培养阳性结果是PTCD围手术期继发胆道感染的独立危险因素。PTCD是采集MOJ胆汁标本的适宜方法。应该根据相关危险因素,制定完善PTCD围手术期胆道感染的预防与治疗策略。MOJ继发感染抗菌药物使用策略应有别于BOJ。
Objective:A retrospective one-center study was conducted to assess the information of bile culture and susceptibility testing special for malignant biliary obstruction and to get the risk factors of biliary system infection after percutaneous transhepatic cholangial drainage (PTCD) in malignant obstructive jaundice (MOJ) patients.
Methods:From August2003to September2010,694patients with malignant biliary obstruction received percutaneous transhepatic cholangial drainage (PTCD). Bile specimens were collected during the procedure of PTCD. Collect the information of gender, age, obstruction time,type of primartumor,site of obstruction, drainage style, tumor stage, hemoglobin, phenotype of peripheral blood mononuclear cell (Treg), bilirubin total, direct bilirubin, albumin, Child-Pugh score, and results of bile culture for Logistic multiplicity.
Results:There are694patients with malignant biliary obstruction in the study. There were485males and209females in the study with an age range of38-78years (mean62). There was no growth on bile culture in57.1%patients (396/694).42.9%patients had a positive bile culture (298/694) and342strains of microorganism were identified. There were156patients(22.3%,156/694) diagnosed by biliary infection.Gram-positive bacteria account for50.9%(174/342) and Gram-negative bacteria account for41.5%(142/342). No anaerobes were cultured in this research. The most frequent microorganisms were Enterococcus faecalis (12.0%,41/342), Escherichia coli (9.9%,34/342), Klebsiella pneumoniae (8.2%,28/342), Staphylococcus epidermidis (5.6%,19/342), Enterococcus (5.3%,18/342) and Enterobacter cloacae (4.7%,16/342). The rate of beta-lactamase producing Gram-positive bacteria was27.6%(48/174) and the rate of Gram-negative bacteria was19.7%(28/142). The rate of enzyme-producing Escherichia coli was61.8%(21/34). The risk factor of biliary system infection after PTCD include age (x2=4.621,p=0.032)、site of obstruction (x2=17.450,p<0.001)、drainage style (x2=14.452,p<0.001)、tumor stage (x2=4.741,p=0.029)、hemoglobin (x2=3.914 p=0.048), Child-Pugh score (x2=5.491,p=0.019), albumin<30g/L(x2=4.776,p=0.029), phenotype of peripheral blood mononuclear cell (Treg)(x2=5.015,p=0.025), results of bile culture(x2=65.381, p<0.001).And results of Logistic multiplicity is the risk factors were drainage style, Child-Pugh score and results of bile culture.
Conclusions:Our findings suggest the bile cultures in malignant biliary obstruction are different from those in Tokyo Guidelines and benign biliary obstruction researches, which indicate antibacterial therapy should be different. The risk factor of biliary system infection after PTCD include age, site of obstruction, drainage style, tumor stage,hemoglobin,Child-Pugh score, phenotype of peripheral blood mononuclear cell (Treg) and results of bile culture. And drainage style, Child-Pugh score and results of bile culture are independent risk factors. Knowledge of the antimicrobial susceptibility data could inform better use of antibiotics for empiric therapy for biliary infection with malignant biliary obstruction.
引文
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[9]郭秀英,郭志,邢文阁等.301例恶性梗阻性黄疸胆汁细菌培养与药物敏感性的临床研究[J].中华检验医学杂志.2009,32(10)：1176-1177
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[1]Coss A, Byrne MF. Preoperative biliary drainage in malignant obstruction: indications, techniques, and the debate over risk[J]. Curr Gastroenterol Rep.2009 Apr; 11 (2):145-9.
[2]Ghoneim E, Refaei AA,et al. Obstructive jaundice promotes intestinal-barrier dysfunction and bacterial translocation:experimental study[J]. Hepatol Int.2007 Dec;1(4):444-8
[3]Moghimi M, Marashi SA, Salehian MT, et al.Obstructive jaundice in Iran: factors affecting early outcome[J]. Hepatobiliary Pancreat Dis Int[J].2008 Oct;7(5):515-9.
[4]Brown KT, Covey AM. Management of malignant biliary obstruction[J]. Tech Vase Interv Radiol.2008 Mar;11(1):43-50.
[5]van Delden OM, Lameris JS. Percutaneous drainage and stenting for palliation of malignant bile duct obstruction[J]. Eur Radiol.2008 Mar;18(3):448-56.
[6]Tanaka A, Takada T, Kawarada Y,et al. Antimicrobial therapy for acute cholangitis:Tokyo Guidelines. J Hepatobiliary Pancreat Surg. 2007;14(1):59-6
[7]Mannella P, Benea G, Addesso F,et al. Culture studies of the bile during transhepatic cholangiography. Minerva Med[J].1985 Oct 27;76(41):1917-20.
[8]Kiesslich R, Holfelder M, Will D, et al. Interventional ERCP in patients with cholestasis[J]. Degree of biliary bacterial colonization and antibiotic resistance. Z Gastroenterol.2001 Dec;39(12):985-92.
[9]郭秀英,郭志,邢文阁等.301例恶性梗阻性黄疸胆汁细菌培养与药物敏感性的临床研究[J].中华检验医学杂志.2009,32(10)：1176-1177
[10]Nomura T, Shirai Y, Hatakeyama K.Impact of bactibilia on the development of postoperative abdominal septic complications in patients with malignant biliary obstruction[J]. Int Surg.1999 Jul-Sep;84(3):204-8.
[11]Englesbe MJ, Dawes LG. Resistant pathogens in biliary obstruction: Importance of cultures to guide antibiotic therapy[J]. HPB (Oxford). 2005;7(2):144-8.
[12]Namias N, Demoya M, Sleeman D,et al. Risk of postoperative infection in patients with bactibilia undergoing surgery for obstructive jaundice[J]. Surg Infect (Larchmt).2005,6(3):323-8
[13]Cipolletta L, Rotondano G, Marmo R,et al. Endoscopic palliation of malignant obstructive jaundice:an evidence-based review[J]. Dig Liver Dis.2007 Apr;39(4):375-88.
[14]Nagino M, Takada T, Miyazaki M,et al.Preoperative biliary drainage for biliary tract and ampullary carcinomas[J]. J Hepatobiliary Pancreat Surg. 2008;15(1):25-30.
[15]Takada T, Kawarada Y, Nimura Y, et al.Background:Tokyo Guidelines for the management of acute cholangitis and cholecystitis[J]. J Hepatobiliary Pancreat Surg.2007;14(1):1-10
[16]l单鸿,罗鹏飞,李彦豪.临床介入治疗学[M]广州：广东科技出版社.1997.23-24
[17]Yoon WJ, Lee JK, Lee KH, et al.A comparison of covered and uncovered Wallstents for the management of distal malignant biliary obstruction. Gastrointest Endosc[J].2006 Jun;63(7):996-1000.
[18]dos Santos JS, Junior WS, Modena JL,et al.Effect of preoperative endoscopic decompression on malignant biliary obstruction and postoperative infection[J]. Hepatogastroenterology.2005 Jan-Feb;52(61):45-7.
[19]. Zeng Y, Xiao L, Yao H, et al. A study of the immune in formation of calcium bilirubinate gallstones in different rabbit models--the changes of the immunoglobulins in serum and bile and the immunoglobulins forming cells in the gallbladder mucoderm[J].Hua Xi Yi Ke Da Xue Xue Bao. 2000 Jun;31(2):155-8.
[20]Scott-Conner CE, Grogan JB.The pathophysiology of biliary obstruction and its effect on phagocytic and immune function[J]. J Surg Res.1994 Aug;57(2):316-36.
[21]Scott-Conner CE, Grogan JB. Serum and cellular factors in murine obstructive jaundice[J]. Surgery.1994 Jan;115(1):77-84.