【作者】 刘冰；

【导师】 过依；

【作者基本信息】 上海交通大学 ， 内科学（呼吸病学）， 2020， 硕士

【摘要】 第一部分:糖尿病合并肺炎克雷伯杆菌肺炎的耐药性、预后和死亡的危险因素研究目的:探讨糖尿病人群和非糖尿病人群中肺炎克雷伯杆菌(Klebsiella pneumoniae,KP)肺炎的耐药性、预后和死亡的危险因素。研究方法:本研究回顾性纳入了从2016年1月到2018年6月间本院KP肺炎住院患者,从院内电子病历系统中整理患者资料,比较了糖尿病人群和非糖尿病人群的KP耐药性和临床预后,并通过logistic回归方法分析两组人群死亡的危险因素。研究结果:本研究纳入了456名KP患者,其中糖尿病组156例,非糖尿病组300例。在糖尿病组中,KP显示出对多种抗生素的低耐药率,包括氨曲南、头孢替坦、舒普深、美罗培南、阿米卡星、妥布霉素、磺胺甲恶唑和磷霉素。在重症监护室(intensive care unit,ICU)中,糖尿病人群感染耐碳青霉烯类肺炎克雷伯杆菌(carbapenem-resistant Klebsiella pneumoniae,CRKP)的比例较非糖尿病人群更低(45.1%vs 63.0%,P=0.038)。糖尿病患者KP肺炎的疾病严重程度和死亡率更高,但糖尿病与KP肺炎死亡非独立相关。多因素回归分析显示,糖尿病组中KP肺炎死亡的危险因素是:男性、血白蛋白<35g/L、血流感染和有创机械通气;在非糖尿病组中是高CURB-65评分、CRKP感染、血流感染和入住ICU。研究结论:在KP肺炎中,与非糖尿病人群相比,糖尿病人群的KP耐药率较低、病情更重、死亡的危险因素也不同。因此,在临床工作中,应该合理而有效的运用抗菌和支持治疗,在降低死亡率的同时,避免增加糖尿病人群对抗生素的耐药性和代谢损伤。第二部分糖尿病合并肺炎克雷伯杆菌肺炎的碳青霉烯类耐药性和毒力特征研究目的:探讨糖尿病合并KP肺炎的碳青霉烯类耐药基因和毒力基因的分布、毒力相关血清型和高黏液表型,以及糖尿病合并CRKP和高毒力肺炎克雷伯杆菌(hypervirulent Klebsiella pneumoniae,Hv KP)肺炎的临床特征、预后和耐药性。研究方法:本研究前瞻性收集了本院2018年12月至2019年6月间KP肺炎患者呼吸道标本检出的KP菌株。从电子病历系统中提取患者临床信息,通过聚合酶链式反应测定常见碳青霉烯类耐药基因(KPC、IMP、NDM-1、VIM和OXA-48)、常见毒力基因(rmp A、aerobactin、all S和wca G)和常见毒力相关血清型基因(K1和K2),通过药敏实验结果探究KP临床耐药表型,通过拉丝实验探究KP高黏液表型。研究结果:本研究共收集了191株KP肺部感染菌株,其中糖尿病组65株,非糖尿病组126株。在ICU中,KPC基因(70.0%vs 40.7%,P=0.012)和CRKP菌株(74.0%vs 48.1%,P=0.023)在非糖尿病人群中的检出率高于糖尿病人群;在非ICU中,Hv KP菌株(aerobactin基因阳性)在糖尿病人群中的检出率高于非糖尿病人群(78.9%vs59.2%,P=0.036)。糖尿病和非糖尿病人群在高黏液性肺炎克雷伯杆菌的检出比例方面无明显差异。另外,4株KP为耐碳青霉烯类且高毒力的肺炎克雷伯杆菌(carbapenem-resistant and hypervirulent Klebsiella pneumoniae,CR-Hv-KP)。在糖尿病组,与Hv KP肺炎患者相比,CRKP肺炎患者中男性比例更高(100%vs 80%,P=0.044)、空腹血糖水平更高(11.3 vs 8.6 mmol/L,P=0.038)。在非糖尿病组,与CRKP肺炎患者相比,Hv KP肺炎患者中合并恶性肿瘤的比例更高(57.7%vs 21.3%,P<0.001)。此外,在两组人群中,CRKP肺炎患者30天内碳青霉烯类抗生素暴露、多部位检出、ICU和死亡/自动出院的比例更高,CURB-65评分更高,住院时长更长。在耐药性方面,CRKP菌株对常用抗生素的耐药性高于非碳青霉烯类耐药且非高毒力的肺炎克雷伯杆菌(non-carbapenem-resistant-non-hypervirulent Klebsiella pneumoniae,non-CR-non-Hv-KP)菌株,而Hv KP菌株对常用抗生素的耐药性低于non-CR-non-Hv-KP菌株。但糖尿病人群和非糖尿病人群的耐药性在CRKP内和Hv KP内无明显差异。研究结论:在罹患KP肺炎时,非ICU中的糖尿病患者更易合并Hv KP感染,ICU中的非糖尿病患者更易合并CRKP感染。CR-Hv-KP也已出现。糖尿病合并症和血糖水平可影响CRKP和Hv KP肺部感染的特征。CRKP肺部感染比Hv KP肺部感染的耐药性更高、病情更重、预后更差。因此,临床中需要加强对KP的有效监控,根据菌株的毒力和耐药特性开展合理的治疗。更多还原

【Abstract】 Part one: Antimicrobial resistance,outcome and risk factors for mortality of Klebsiella pneumoniae pneumonia among diabeticsObjectives: This study aimed to investigate antimicrobial resistance,prognosis,and risk factors for mortality of Klebsiella pneumoniae(KP)pneumonia in diabetics and nondiabetics.Methods: A retrospective study was conducted among inpatients of KP pneumonia via electronic medical records in a territory hospital between January 2016 and June 2018.Antimicrobial resistance and prognosis in KP pneumonia were compared between diabetics and nondiabetics.Independent risk factors for mortality in KP pneumonia were identified by univariate and multivariate logistic regression among diabetics and nondiabetics separately.Results: In this study,456 patients with KP pneumonia were included.There were 156 cases with diabetes and 300 without diabetes.KP showed a lower antimicrobial resistance to a multitude of antimicrobials in pneumonia among diabetics than nondiabetics,namely aztreonam,cefotetan,sulperazone,meropenem,amikacin,tobramycin,sulfamethoxazole,and fosfomycin.Carbapenem-resistant Klebsiella pneumoniae(CRKP)was more prevalent among nondiabetics than diabetics who were admitted to intensive care unit(ICU)(63.0% vs 45.1%,P=0.038).The disease severity and mortality of KP pneumonia were higher in diabetic patients,while diabetes was not independently associated with mortality of KP pneumonia.Multivariable analysis showed that independent risk factors for in-hospital mortality in KP pneumonia among diabetics differed from that among nondiabetics as well. Independent predictors for in-hospital mortality of KP pneumonia among diabetics were male(OR: 5.89,95% CI: 1.34-25.93,P=0.019),albumin<35 g/L(OR: 7.00,95% CI: 2.02-24.28,P=0.002),bloodstream infection(BSI)(OR: 21.14,95% CI: 3.18-140.72,P=0.002),and invasive ventilation during hospitalization(OR: 8.00,95% CI: 2.99-21.42,P<0.001).In nondiabetics,independent predictors were higher CURB-65 score(OR: 1.92,95% CI: 1.29-2.86,P=0.001),CRKP(OR: 2.72,95% CI: 1.07-6.90,P=0.035),BSI(OR: 4.98,95% CI: 1.34-18.50,P=0.017),and ICU admission(OR: 4.06,95% CI: 1.57-10.47,P=0.004).Conclusion: In KP pneumonia,diabetics showed lower antimicrobial resistance,higher severity and mortality,and different independent risk factors for mortality compared with nondiabetics.Importantly,further attention should be paid on rational and effective antibiotic and supportive treatments in order to reduce mortality without aggravating antimicrobial resistance and metabolic damage among diabetics.Part two: Carbapenem resistance and virulence characteristics of Klebsiella pneumoniae pneumonia among diabeticsObjectives: This study aimed to explore the distribution of carbapenem resistance genes,virulence genes,virulence associated capsular serotypes and hypermucoviscous phenotype;and clinical characteristics,prognosis and antibiotic resistance of CRKP pneumonia and hypervirulent Klebsiella pneumoniae(Hv KP)pneumonia among diabetics and nondiabetics.Methods: KP strains were prospectively collected from lower respiratory tract samples of KP pneumonia patients in a territory hospital from December 2018 to June 2019.Clinical information of patients was extracted from electronic medical record system.Common carbapenem resistance genes(KPC,IMP,NDM-1,VIM and OXA-48),virulence genes(rmp A,aerobactin,all S and wca G)and virulence related serotype(K1 and K2)genes were detected by Polymerase Chain Reaction.Antimicrobial resistance of KP was explored by drug sensitivity test,and hypermucoviscous phenotype by string test.Results: 191 KP strains causing pneumonia were collected in this study,including 65 strains in diabetics and 126 in nondiabetics.In ICU,KPC gene(70.0% vs 40.7%,P=0.012)and CRKP strain(74.0% vs 48.1%,P =0.023)were more frequently isolated among nondiabetics than diabetics.In non-ICU,Hv KP strain(aerobactin gene positive)was more frequently isolated among diabetics than nondiabetics(78.9% vs 59.2%,P =0.036).Isolation rate of hypermucoviscous Klebsiella pneumoniae was comparable among diabetics and nondiabetics.Besides,4 carbapenem-resistant and hypervirulent Klebsiella pneumoniae(CR-Hv-KP)strains were isolated.In diabetics,there were more male patients(100% vs 80%,P=0.044)and higher fasting blood glucose level(11.3 vs 8.6 mmol/L,P=0.038)in CRKP pneumonia than in Hv KP pneumonia.In nondiabetics,patients with Hv KP pneumonia had a higher proportion of malignant tumors(57.7% vs 21.3%,P<0.001).In addition,in both diabetics and nondiabetics,patients with CRKP pneumonia had higher rates of carbapenem exposure within 30 days,multisystem detection,ICU admission,and death/automatic discharge,higher CURB-65 score,and longer length of hospital stay.With regard to antimicrobial resistance,resistance of KP to commonly used drugs was higher in CRKP than non-carbapenem-resistant-non-hypervirulent Klebsiella pneumoniae(non-CRnon-Hv-KP),and that of Hv KP was lower than non-CR-non-Hv-KP.No significant differences in antimicrobial resistance were found in CRKP strain among diabetics and nondiabetics,nor in Hv KP strain.Conclusion: In KP pneumonia,diabetics were more prone to Hv KP infection in non-ICU,and nondiabetics were more prone to CRKP in ICU.CR-Hv-KP had also appeared.Diabetes and blood glucose level could affect characteristics of CRKP and Hv KP pneumonia.CRKP pneumonia was of higher antibiotic resistance,higher severity and worse prognosis than Hv KP pneumonia.Accordingly,it is necessary to strengthen the effective monitoring of KP in clinical practice,and carry out reasonable treatment according to the virulence and drug resistance characteristics of KP strains.更多还原