耐药GNB感染抗菌治疗

耐药革兰阴性菌感染的抗菌治疗,2,Gram-negative bacilli account for over 70% of all clinical isolates in China,Gram-negative bacilli70（62297/88778）,Gram-positive cocci30（26481/88778）,CHINET 2015,Percentage of Gram-negative bacilli in total clinical isolates (%),CHINET national bacterial resistance surveillance data,革兰阴性菌的构成,CHINET 2007-2014,4,4,Constituent ratio of A. baumannii, P. aeruginosa and K. pneumoniae among all clinical isolates in China since 2005,CHINET national bacterial resistance surveillance data,%,Hu FP, Clin Microbiol Infect 2016; 22: S9S14,P. aeruginosa,K. pneumoniae,A. baumannii,5,5,Corelation of increasing trends of imipenem-resistance with constituent ratio of K. pneumoniae clinical isolates in China since 2005,Ratio%,Modified from Hu FP, Clin Microbiol Infect 2016; 22: S9S14,Imipenem-resistance rate,Constituent ratio,CR%,CHINET DATA,6,6,Corelation of increasing trends of imipenem-resistance with constituent ratio of A. baumannii clinical isolates in China since 2005,Ratio%,Modified from Hu FP, Clin Microbiol Infect 2016; 22: S9S14,Imipenem-resistance rate,Constituent ratio,CR%,CHINET DATA,7,7,Corelation of increasing trends of imipenem-resistance with constituent ratio of P. aeruginosa clinical isolates in China since 2005,Ratio%,Modified from Hu FP, Clin Microbiol Infect 2016; 22: S9S14,Imipenem-resistance rate,Constituent ratio,CR%,CHINET DATA,8,A report of bacterial resistance in China 20052014,Antimicrobial resistance in five most common bacteria: E. coli, K. pneumoniae, A. baumannii, P. aeruginosa and S. aureus,Hu FP, Clin Microbiol Infect 2016; 22: S9S14,MDR-Multiple-drug resistant, 多重耐药：对3类或以上在抗菌谱范围内的抗菌药耐药XDR-Extensively drug resistant, 广泛耐药：除1-2个抗菌药敏感外，均耐药PDR-Pan-drug resistant，全（泛）耐药：对当前临床应用的所有抗菌药耐药,9,MDR、XDR、PDR的定义,主题词,Magiorakos AP, Clin Microbiol Infect 2012,18: 268,OUTLINE,肠杆菌科细菌老问题：产ESBL新问题：产碳青霉烯酶非发酵糖细菌习惯了的问题：XDR鲍曼不动杆菌变化不大的问题：铜绿假单胞菌嗜麦芽窄食单胞菌,肠杆菌科细菌耐药问题：最需关注的-内酰胺酶是ESBLs,超广谱-内酰胺酶(ESBLs)高产头孢菌素酶(AmpC酶)产碳青霉烯酶（KPC、NDM-1等）,MDRXDR orPDR,Prevalence of ESBL in Enterobacteracae肠杆菌科细菌ESBL检出率,CHINET Data,产与非产ESBLs大肠埃希菌的耐药率（%）Comparison of antimicrobial resistance between ESBL+ and ESBL- isolates,CHINET 2014,胡付品, 中国感染与化疗杂志 2015; 15(5): 401,产与非产ESBLs克雷伯菌属的耐药率（%）,CHINET 2014,产ESBL菌株感染的抗菌药物选择,碳青霉烯类（亚胺培南、美罗培南、帕尼培南、厄他培南、比阿培南）：为最有效的药物，用于重症及/或有基础疾病感染患者酶抑制剂合剂：用于轻中度感染头霉素类：临床疗效不满意，用于腹腔、盆腔手术的预防用药阿米卡星、环丙沙星：多用于联合用药,15,碳青霉烯类耐药肠杆菌科细菌,CRE=carbapenam-resistant enterobacteriacaeCPE=carbapenamase-producing enterobacteriacae,16,主题词,17,Increasing trend of carbapenem-resistant Klebsiella spp. 碳青霉烯类耐药克雷伯菌属（CRE）显著上升趋势,CHINET Data,肠杆菌科细菌与鲍曼不动杆菌的比较,18,XDR、PDR肠杆菌科细菌的抗菌治疗,多黏菌素（国内无供应）替加环素（常需合用）磷霉素的联合治疗（多粘、替加、碳青霉烯、氨基糖苷）（头孢他啶、头孢吡肟）克拉维酸（对KPC有一定的抑制作用）？氨曲南阿米卡星？（产金属酶包括NDM-1部分菌株仍对此2药敏感）新抗菌药：头孢他啶/阿维巴坦,19,结论：治疗CRE尚无理想的抗菌药物,20,各治疗方案对产碳青霉烯酶肺炎克雷伯菌感染的失败率,A, 2种抗菌药联合，包括碳青霉烯类B, 2种抗菌药联合，不包括碳青霉烯类 C, 单用氨基糖苷类D,单用碳青霉烯类E, 单用替加环素F, 单用黏菌素G, 无有效治疗药物,Clin Microbiol Rev 2012; 25: 6827,单用粘菌素,单用替加环素,21,XDR肠杆菌科细菌感染的联合治疗方案,Chinese XDR Consensus Working Group. Clin Microbiol Infect 2016; 22: S15S25,22,粘菌素异质性耐药和鲍曼不动杆菌耐药率全球报告,J Antimicrob Chemother 2012; 67: 16071615,异质性耐药率为19100%耐药率为046%,问题、异质性耐药,23,替加环素治疗MDR肺炎克雷伯和鲍曼不动杆菌感染的优缺点,Kollef M,Crit Care 2013; Freire A Diagn Microbiol Infect Dis 2010;Poulakou G Journal Infect 2009; Pournaras S.UAA 2010; Souli M CID 2010;Wiskirchen DE AAC 2011; Burkhardt O, IJAA 2009; Koomanachai P AAC 2009; Giamarellou and Poulakou Expert Opin Drug Metab Toxicol 2011Hirsch and Tamm 2010.,替加环素对革兰阴性菌为抑菌作用在血液、尿液和肺泡上皮衬液中的药物浓度较低对VAP的试验结果欠佳,在体外与美罗培南和粘菌素有协同作用加大剂量可达到目标PK/PD替加环素联合给药在临床应用中得到满意疗效高剂量治疗HAP的期临床研究显示出满意疗效,(-),(+),24,碳青霉烯类不单用治疗MIC4mg/L菌株的感染， 4 mg/L菌株尽量避免单用 碳青霉烯类治疗CRE应注意以下几点：碳青霉烯类 MIC 8mg/L与其他抗菌药联合应用如多粘菌素、替加环素、氨基糖苷类大剂量、延长输注时间（34小时）,Daikos 17:1135.,碳青霉烯类可用于CRE的治疗但是带“尾巴”,25,产KPC肺克对磷霉素的敏感率高包括替加环素和/或粘菌素不敏感菌株,* CLSI：64 g/ml定义为敏感 EUCAST：32 g/ml定义为敏感,Endimiani A, et al. AAC 2010; 54: 526-9Falagas ME, et al. IJAA 2010; 35: 240,国内，CR-Kp的敏感率40%50%,新抗菌药：内酰胺酶抑制剂Avibactam (NXL104),对A类及C类内酰胺酶具广谱抑制作用包括KPC碳氢酶烯酶Avibactam与头孢他啶的合剂对多重耐药肠杆菌科细菌包括产ESBL及丝氨酸碳氢霉烯酶KPC有效Avibactam 与头孢他啶的合剂（Azycaz）美国FDA 2015. 2. 25批准上市Avibactam 与ceftaroline的合剂正在进行治疗复杂性尿路感染及复杂性腹腔感染的临床试验,26,例、CRE血流感染,男，45y头颈部、双侧上肢大面积烧伤继发感染：皮肤、肺部、血流三个部位细菌培养：XDR鲍曼不动杆菌药敏：替加环素S、多粘菌素S、阿米卡星S、头孢哌酮舒巴坦S，其他均耐药抗菌治疗：替加环素+头孢哌酮舒巴坦热退好转，1周后又出现发热,27,例、CRE血流感染,血培养为碳青霉烯类耐药肺炎克雷伯菌，此前2天皮肤分泌物、痰培养同样细菌血肌酐值180 umol/L药敏：多粘菌素S、阿米卡星S，其他均R问题：如何调整用药？多粘菌素,28,例、CRE血流感染,与哪个抗菌药联合？加做抗菌药MIC碳青霉烯类：美罗培南或亚胺培南磷霉素其他SMZco阿米卡星,29,OUTLINE,肠杆菌科细菌老问题：产ESBL新问题：产碳青霉烯酶非发酵糖细菌习惯了的问题：XDR鲍曼不动杆菌变化不大的问题：铜绿假单胞菌嗜麦芽窄食单胞菌,31,Treads of percentages of 3 principal non-fermenter bacteria among non-fermenters in Shanghai region,Decreasing trend for P. aeruginosa,Increasing trend for Acinetobacter spp.,Relatively stable for S. maltophilia,Changing trends of constituent ratio of P. aeruginosa, Acinetobacter spp. and S. maltophilia in Gram-negative bacilli in Shanghai,8769株不动杆菌属(鲍曼不动93.0%)的耐药率（%）,Resistance rates to most antimicrobials in Acinetobacter spp. are 50%不动杆菌属对多数抗菌药的耐药率50%,CHINET 2014,不同耐药水平鲍曼不动杆菌的抗菌治疗,非多重耐药菌感染敏感的内酰胺类抗菌药根据药敏试验结果选用其他敏感抗菌药多重耐药菌感染碳青霉烯类舒巴坦或含舒巴坦合剂碳青霉烯类耐药菌感染多粘菌素与利福平等其他抗菌药合用对于有气管支气管炎或呼吸机相关性肺炎者，可用多粘菌素雾化吸入替加环素对于考虑由复数菌引起的复杂性腹腔感染及皮肤软组织感染，可作为首选药物,WangMG,33,Curr Opin Infect Dis 2010; 23: 332,Controversies on the combination therapy for XDR or PDR A. baumannii infections,Support Necessary for combination: Treatment options are limitedPotential advantages of combination: improved efficacy due to synergy Combination therapy is commonly used in clinical practice,34,Opposition Lack of large randomized clinical trial data (evidence-based data)Disadvantages of combinationadverse eventspotential drive towards resistance,Paul M, J Antimicrob Chemother 2014; 69: 23059,35,XDR鲍曼不动杆菌感染的联合抗菌治疗方案,Chinese XDR Consensus Working Group. Clin Microbiol Infect 2016; 22: S15S25,Antimicrobial treatment of XDR A. baumannii at a hospital in Shanghai,Antimicrobial therapy of 43 pts with XDR A. baumannii was retrospectively analyzedConclusion: High-dose cefoperazone-sulbactam and carbapenem alone or combined with other antibiotics could be considered choices for treatment of XDR when other options are not available.,36,Li Y, J Microbiol Immunol Infect 2015; 48, 101-8,美罗培南+头孢哌酮舒巴坦+米诺环素治疗PDR鲍曼不动杆菌重度烧伤感染,9例，6M3F, 3811Y，均有吸入烧伤PDR鲍曼感染：9例首先出现肺部，6例皮肤（其中4例血流）抗菌药剂量：美罗培南 6g/d头孢哌酮舒巴坦 12 g/d米诺环素 0.2 g/d PO疗效：全部有效,37,Ning F, Chin J Med 2014; 127(6):1177,Cefoperazone-sulbactam (CFP-SUL) and Sulbactam,Relatively low resistance rate of CFP-SUL in A. baumannii The resistance rate is lower than ampicillin-sulbactam: 38% vs 67% in 2015 (unpublished CHINET data) The antimicrobial susceptibility of CFP-SUL is routinely tested for gram-negative bacilli in ChinaCFP-SUL is available in several Asian countries such as China, Japan, Korea, Thailand and Phillipines. Sulbactam alone available since 2014 in ChinaBreakpoints of CFP-SUL used: S, 16/8 g/ml; I, 32/16 g/ml; R, 64/32 g/ml (Jones RN, JCM 1987),38,CHINET national bacterial resistance surveillance data,CFP-SUL resistance rate in A. baumannii,R%,39,39,A. baumannii including XDR isolates have a relatively high susceptible rate to minocycline in China,CHINET national bacterial resistance surveillance data,R%,Hu FP, Clin Microbiol Infect 2016; 22: S9S14,n,S, 4 g/ml,MIC distribution of minocycline against 256 XDRABCARSS national bacterial resistance surveillance data,Xu A, Clin Microbiol Infect 2016; 22: S1-8,The use of Minocycline or Doxycycline for Acinetobacter infections,Minocycline is an “old drug” that was first introduced in the 1960s. It is approved for the treatment of A. baumannii infections by FDA of the US. In China, Minocycline is only available for oral formulation, but has both oral and intravenous preparations of Doxycycline. Minocycline susceptibility is routinely tested for AcinetobacterIntravenous doxycycline is used for XDR A. baumannii infections. Usually combined with CFP-SUL, carbapenems, or with both of them,40,Goff DA 59: s365-6,What is the difference between doxycyline and minocycline?,41,Castanheira M. Clin Infect Dis 2014; 59: s367-73,Doxycycline may have less central nervous adverse effect of dizziness,A. baumannii clinical isolates are highly susceptible to both of themMinocycline has better activity (n=5478),42,42,上海地区铜绿假单胞菌对抗菌药的耐药率相对稳定,Shanghai Surveillance data,%,43,43,%,CHINET DATA,Pan-drug resistance (PDR) in P. aeruginosa and A. baumannii (colistin and tigecycline not included for AST),铜绿假单胞菌感染的抗菌药物选择,青霉素类： 哌拉西林、美洛西林、阿洛西林头孢菌素类：头孢他啶、头孢哌酮、头孢吡肟酶抑制剂合剂：头孢哌酮-舒巴坦 哌拉西林-他唑巴坦 替卡西林-克拉维酸碳青霉烯类：亚胺培南、美罗培南、帕尼培南氟喹诺酮类：环丙沙星氨基糖苷类：阿米卡星、庆大霉素,铜绿假单胞菌感染治疗原则,剂量足 high dosage疗程足 long treatment course联合 combination-内酰胺药物+氨基糖苷类：协同，后者不良反应大-内酰胺药物+环丙沙星：无协同，后者组织浓度高， 抑制biofil