革兰阴性菌耐药及治疗课件

1、革兰阴性菌耐药及治疗抗生素Antibiotic抗微生物药物 Antimicrobial agents抗菌药抗病毒药抗菌药物 Antibacterial agents抗生素合成抗菌药抗感染药物 Anti-infectives抗微生物药抗寄生虫药几个概念临床常用抗菌药物-内酰胺类（-lactams）抗生素氨基糖苷类（Aminoglycesides）抗生素 大环内酯类（Macrolides）抗生素 喹诺酮类（Quinolones）药物 糖肽类（Glycopeptides ）抗生素恶唑烷酮类（Oxazolidine）其他类抗菌药物 革兰阳性菌 革兰阴性菌细菌分类、命名及药敏报告革兰染色：丹麦Chris

2、tain Gram(1884)细菌初步分类 G+coccus G+ G+bacillus G G-coccus G- G-bacillus细菌分类与命名林奈双命名法：属名+种名 Staphylococcus aureus 金黄色葡萄球菌 Escherichia Coil 大肠埃希菌最基本分类单位：种 洋葱伯克霍尔德菌亚种、型、群 木糖产碱杆菌木糖氧化亚种 大肠埃希菌：ETEC、EIEC、EHEC、EPEC、 A、B、C、G、D群链球菌 抗菌药物敏感试验 Antibiotic susceptibility test,AST84021 Tetracycline (ug/ml)MIC = 2 ug/

3、mlDetermination of MICChlAmpEryStrTetDisk Diffusion Test纸片扩散法（K-B法） 药敏标准不一致也有差异CLSI与UCARST折点不一样通用定义：对三种以上不同类别的抗菌药物耐药的细菌 多重耐药菌（MDR）：不同菌种 定义不完全一致 多重耐药菌（Multidrug-resistance)： 对以下3类抗菌药物耐药抗假单胞菌头孢菌素（头孢他啶、头孢吡肟）抗假单胞菌碳青霉烯类抗生素（亚胺培南、美罗培南）含有内酰胺酶抑制剂的复合制剂氟喹诺酮类氨基糖苷类Clin Infect Dis 2006; 43 Suppl 2: S43-8Clin Micr

4、obiol Rev 2008; 21: 538-82N Engl J Med 2008; 358: 1271-81针对主要非发酵菌MDR-PDR-XDRMDRMulti Drug ResistantPDRPan Drug Resistant(泛耐药)XDRExtensive Drug Resistant(大量/广泛/大规模耐药)Extreme Drug Resistant(极端/极度耐药)XDR vs XDRXDRTextresistance to all but 1 or 2Extensive Drug ResistantExtreme Drug Resistantcompleteloss

5、of antibiotic optionsMatthew E. Falagas, et al. CID 2008:46(1): 1121-1122David L. Paterson, et al. CID 2007:45 (1) :1179-1181MDR XDR PDRXDRPDRXDRMDRExtreme drug resistantPan drug resistantExtensive drug resistantMulti drug resistantXDRPDRMDRresistance to 3 classes of antimicrobial agentsresistance t

6、o all but 1 or 2resistance to allamong those drugsavailable at the time in most parts of the world potentially effectiveMatthew E. Falagas, et al. CID 2008:46(1): 1121-1122Antipseudomonal penicillinsCephalosporinsCarbapenemsMonobactamsQuinolonesAminoglycosides PolymyxinsPDRP. aeruginosa A. baumannii

7、 Antipseudomonal penicillinsCephalosporinsCarbapenemsMonobactamsQuinolonesAminoglycosides PolymyxinsSulbactamTetracyclineTigecyclineMatthew E. Falagas, et al. JMM, 2006, 55, 16191629当今世界主要的MDR 、 XDR 、 PDR1.甲氧西林耐药金葡菌(MRSA)2.万古霉素耐药肠球菌(VRE)和金葡菌(VRSA)3.产超广谱-内酰胺酶(ESBLs) 大肠埃希菌和肺炎克雷伯菌4.高产头孢菌素酶肠杆菌科细菌5.多重耐药

8、耐药 铜绿假单胞菌和鲍曼不动杆菌多重耐药菌流行时期感染治疗有效性细菌耐药性增加Antibiotic treatment A balancing actAppropriate initial antibiotic treatmentAvoidunnecessaryantibioticsNot Just Appropriate Therapy: RAPID Therapy in Septic ShockDelay in treatment (hours) from hypotension onset to effective antimicrobial therapySurvivial (%)Ea

9、ch hour of delay carries 7.6% reduction in survivalKumar et al. Crit Care Med 2006; 34:1589-1596.2154 patients with septic shock78.9% got effective antimicrobial therapy迅速的合理的治疗重要吗？ 产ESBLs的大肠埃希菌、肺炎克雷伯菌和奇异变形杆菌引起的菌血症21天病死率Tumbarello et al, Antimicrob Agents Chemother 51: 1987 94, 2007定义：首次血培养阳性， 72小时后

10、应用体外敏感的抗菌药物进行初次治疗。Does Inappropriate Therapy Result From Antibiotic Resistance?Inappropriate therapy is more likely if antibiotic resistance is presentAntibiotic-resistant organisms are more commonly associated with inappropriate therapyAdapted from Kollef MH. Clin Infect Dis. 2000;31(suppl 4):S131S

11、138.Inappropriate treatment (%)010203040Acinetobacterspp.Pseudomonas aeruginosaS. aureusOtherKlebsiella pneumoniae肠杆菌科细菌 临床关注的主要-内酰胺酶超广谱-内酰胺酶(ESBLs)高产头孢菌素酶(AmpC酶)极少数菌株产碳青霉烯酶 (碳青霉烯酶KPC)MDRXDR产ESBLs菌株血行感染死亡率显著增加（Meta分析）产ESBLs菌株与不产ESBLs菌株血行感染死亡率比较的Meta分析包括16个研究产ESBLs菌株菌血症死亡率显著增加(pooled RR 1.85, 95% CI

12、1.392.47, P 0.001） Mortality and delay in effective therapy associated with extended-spectrum b-lactamase production in Enterobacteriaceae bacteraemia: a systematic review and meta-analysis. Journal of Antimicrobial Chemotherapy (2007) 60, 913920病人伴发热感染性疾病非感染性疾病病毒细菌结核真菌寄生虫GG疗效好疗效不好停药或降阶梯调 整根据耐药状况经验性

13、治疗取相应标本进行病原学检测根据检测结果调整抗生素临床病情的判定 发热（38C）或低温（36C） 寒战 白细胞增多（计数大于10，000109/L，特别有“核 左移” 未成熟的或杆状核的白细胞） 粒细胞减少（成熟的多核白细胞512512512100%PRL/CA#8-51225651230%20%50%TZP64-512128512030%70%TZP/CA8-5121651255%20%25%SCF16-128641285%25%75%SCF/CA0.5-3223285%15%0%CEP256256256100%CEP/CA1-256425670%10%20%CAZ8-2561625615%

14、50%35%CAZ/CA1-128412875%25%CTX64-2561282560%100%CTX/CA2560.2525675%25%CN0.5-256825645%55%AK2-256425650%50%FEP25670%525%IMP0.06-640.256490%10%CIP2561625640%60%FOX2-256425660%535%产ESBLs菌株血行感染：病死率增加的危险因素之一广谱头孢菌素的治疗Bloodstream Infections Due to Extended-SpectrumBeta-Lactamase-Producing Escherichia coli

15、and Klebsiella pneumoniae:Risk Factors for Mortality and Treatment Outcome, with SpecialEmphasis on Antimicrobial Therapy. AAC. 2004, 48,(12),p. 45744581产ESBLs菌株血行感染：头孢菌素的经验性治疗疗效判断与MIC的相关性Bloodstream Infections Due to Extended-SpectrumBeta-Lactamase-Producing Escherichia coli and Klebsiella pneumoni

16、ae:Risk Factors for Mortality and Treatment Outcome, with SpecialEmphasis on Antimicrobial Therapy. AAC. 2004, 48,(12),p. 45744581Susceptible：MIC=8ug/mlMICs =8 ug/ml折点？头孢他啶对产ESBLs菌株MIC分布产ESBLs菌株感染：头孢菌素的经验性治疗疗效判断与MIC的相关性ESBLs检测？更改折点临床病例资料ESBLs检测的必要性抗菌药物的选择 头孢菌素治疗对其敏感的产ESBLs菌株的严重感染仍导致治疗的失败 临床微生物实验室指导临

17、床合理选择抗菌药物产ESBLs菌株的严重感染不适合选择头孢菌素作为起始经验性治疗！（即使药敏提示敏感）产ESBLs菌株血行感染：不同抗菌药物经验性治疗疗效比较氟喹诺酮类部分临床研究证实环丙沙星治疗产ESBLs菌株感染的有效性但产ESBLs合并对氟喹诺酮类耐药菌株迅速增加！中国台湾，20% 的产ESBL肺炎克雷伯菌对环丙沙星耐药亚洲其他地区的产ESBLs菌株环丙沙星耐药率很高美国，产ESBLs合并环丙沙星耐药菌株的爆发流行，如1999年15家医院中的34肺克产ESBLs，其中仅42对环丙沙星敏感尤其是中国大陆Bell JM, et al. Prevalence of extended spect

18、rum b-lactamase (ESBL)-producing clinical isolates in the Asia-Pacific region and South Africa: regional results from SENTRY Antimicrobial Surveillance Program (199899). Diagn Microbiol Infect Dis 2002; 42:1938. Yu WL, et al. Molecular epidemiology of extendedspectrum b-lactamase-producing, fluoroqu

19、inolone-resistant isolates of Klebsiella pneumoniae in Taiwan. J Clin Microbiol 2002; 40:46669.Quale JM, et al. Molecular epidemiology of a citywide outbreak of extended-spectrum b-lactamaseproducing Klebsiella pneumoniae infection. Clin Infect Dis 2002; 35:83441.产ESBLs菌株血行感染：不同抗菌药物经验性治疗疗效比较Clinical

20、 Infectious Diseases 2003; 39:317碳青霉烯类抗生素产ESBLs菌株血行感染：不同抗菌药物经验性治疗疗效比较不同抗菌药物治疗方案30天病死率比较 ：Thirty-day mortality rates碳青霉烯类 12.9% (8 of 62)环丙沙星 10.3% (3 of 29）头孢菌素 26.9% (7 of 26)氨基糖苷类26.9% (7 of 26)选择碳青霉烯类抗生素作为产ESBLs菌株感染的经验性治疗的合理性！Bloodstream Infections Due to Extended-SpectrumBeta-Lactamase-Producing

21、 Escherichia coli and Klebsiella pneumoniae:Risk Factors for Mortality and Treatment Outcome, with SpecialEmphasis on Antimicrobial Therapy. AAC. 2004, 48,(12),p. 45744581存活率产ESBLs菌株感染：抗菌药物的选择产ESBLs菌株感染：非碳青霉烯类抗生素治疗病死率高于碳青霉烯类抗生素头孢菌素治疗与产ESBLs菌株血行感染疗效较差头孢菌素治疗对其敏感的产ESBLs菌株的严重感染疗效仍差更慎重的选择碳青霉烯类抗生素作为治疗产ESB

22、Ls菌株感染的起始治疗的合理性！根据病人的疾病及病情根据微生物的耐药性Reference：Cheol-In Kang et al. Bloodstream Infections Due to Extended-Spectrum Beta-Lactamase-Producing Escherichia coli and Klebsiella pneumoniae: Risk Factors for Mortality and Treatment Outcome, with Special Emphasis on Antimicrobial Therapy. AAC. 2004, 48,(12),

23、p. 45744581Schiappa et al. Ceftazidime-resistant Klebsiella pneumoniae and Escherichia coli bloodstream infection: a case-control and molecular epidemiologic investigation. J. Infect. Dis. 1996. 174:529536.Wong-Beringer et al. Molecular correlation for the treatment outcomes in bloodstream infection

24、s caused by Escherichia coli and Klebsiella pneumoniae with reduced susceptibility to ceftazidime. Clin. Infect.Dis. 2002. 34:135146.Lautenbach, E., et al. Extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae: risk factors for infection and impact of resistance on ou

25、tcomes. Clin. Infect. Dis. 2001. 32:11621171.DAVID L. PATERSON,et al. Outcome of Cephalosporin Treatment for Serious Infections Due to Apparently Susceptible Organisms Producing Extended-Spectrum b-Lactamases: Implications for the Clinical Microbiology Laboratory.JCM 2001,39:2206-2212产ESBLs菌株感染: 抗菌药

26、物的选择Extended-Spectrum -Lactamases: a Clinical UpdateCLINICAL MICROBIOLOGY REVIEWS, Oct. 2005, p. 657686根据病人的疾病及病情选择抗菌药物国内ESBLs菌株感染治疗1. 严重感染的病人：碳青霉烯类；2. 轻中度的感染：可选择复合制剂（舒普深或特治星），应用时剂量应适当加大；疗效不佳 时可改碳青霉烯类；3. 头霉素也可应用，但耐药比国外严重；4. 环丙沙星85%左右耐药；阿米卡星50%左右耐药。Prevalence of ESBLsCHINET surveillance, China, 2005-

27、2008各地区产ESBL大肠和肺克的检出率大肠=152株肺克=83株产ESBLs大肠和肺克的耐药率大肠=152株肺克=83株患者，男性，58岁，因右上腹不适一周伴发热五天（头孢呋辛4天）血常规：16.2 *10E9/L, N(92%)CRP218mg/L胆石症，胆道感染败血症？何种抗菌药物？选碳青霉烯类对吗?肝脓疡 男性，50岁，临安人发热，白细胞高，CRP高 B超，CT报告肝脓疡头孢曲松和甲硝唑舒普深但白细胞，CRP仍高B超，CT报告肝脓疡基本吸收如何处理？如果是腹腔,胆道,泌尿道感染时:经验性治疗首先要覆盖:大肠埃希菌肺炎克雷伯菌China : 7-Centre survey% resis

28、tance(community)All(1651)E. coli(953)Klebsiella(357)EnterobacterCitrobacter, Serratia (175)ESBL +ve?1617?Imipenem0000Ertapenem0000Cefotaxime14.714.415.425.1Ceftazidime(5.9)(2.7)(8.1)20.0Pip/taz9.57.113.221.7Ciprofloxacin40.850.625.222.9Ling et al AAC 2006, 50, 374 Species Distribution of GNB Causing

29、 IAIs 2,292 Isolates, China, SMART, 2002-2007 Rates of ESBL-producing E. coli and K. pneumoniae from Community-onset (Data from SMART 48 h in China)MICMIC024680.11.010.0100.0Concentration(mcg/mL)Time (h)Rapid Infusion (30 min)Extended Infusion (3 h)Meropenem 500 mg Administered as a 0.5-Hour or 3-Ho

30、ur InfusionMICMICMICTreatment of Multidrug Resistant Burkholderia cepacia With Prolonged Infusion MeropenemMeropenem 2 g infused over 3 hours q 8 hTime (h)Concentration (mcg/mL)08162432400.1110100MIC = 16 mcg/mLTMIC exposure was 40% and 52% of the dosing interval at MICs of16 and 8 mcg/mL, respectively.Kuti JL, et al. Pharmacotherapy 2004;24:1641-5.MIC = 8 mcg/mLTime Above MIC Predicts -lactam EfficacyBacteriostatic and bactericidal activity of -lactams depend on duration of time that free drug levels exceed MIC1Carb