革蘭陰性菌耐藥及治療課件

1、革蘭陰性菌耐藥及治療抗生素Antibiotic抗微生物藥物 Antimicrobial agents抗菌藥抗病毒藥抗菌藥物 Antibacterial agents抗生素合成抗菌藥抗感染藥物 Anti-infectives抗微生物藥抗寄生蟲藥幾個概念臨床常用抗菌藥物-內(nèi)酰胺類（-lactams）抗生素氨基糖苷類（Aminoglycesides）抗生素 大環(huán)內(nèi)酯類（Macrolides）抗生素 喹諾酮類（Quinolones）藥物 糖肽類（Glycopeptides ）抗生素惡唑烷酮類（Oxazolidine）其他類抗菌藥物 革蘭陽性菌 革蘭陰性菌細(xì)菌分類、命名及藥敏報告革蘭染色：丹麥Chris

2、tain Gram(1884)細(xì)菌初步分類 G+coccus G+ G+bacillus G G-coccus G- G-bacillus細(xì)菌分類與命名林奈雙命名法：屬名+種名 Staphylococcus aureus 金黃色葡萄球菌 Escherichia Coil 大腸埃希菌最基本分類單位：種 洋蔥伯克霍爾德菌亞種、型、群 木糖產(chǎn)堿桿菌木糖氧化亞種 大腸埃希菌：ETEC、EIEC、EHEC、EPEC、 A、B、C、G、D群鏈球菌 抗菌藥物敏感試驗 Antibiotic susceptibility test,AST84021 Tetracycline (ug/ml)MIC = 2 ug/

3、mlDetermination of MICChlAmpEryStrTetDisk Diffusion Test紙片擴(kuò)散法（K-B法） 藥敏標(biāo)準(zhǔn)不一致也有差異CLSI與UCARST折點不一樣通用定義：對三種以上不同類別的抗菌藥物耐藥的細(xì)菌 多重耐藥菌（MDR）：不同菌種 定義不完全一致 多重耐藥菌（Multidrug-resistance)： 對以下3類抗菌藥物耐藥抗假單胞菌頭孢菌素（頭孢他啶、頭孢吡肟）抗假單胞菌碳青霉烯類抗生素（亞胺培南、美羅培南）含有內(nèi)酰胺酶抑制劑的復(fù)合制劑氟喹諾酮類氨基糖苷類Clin Infect Dis 2006; 43 Suppl 2: S43-8Clin Micr

4、obiol Rev 2008; 21: 538-82N Engl J Med 2008; 358: 1271-81針對主要非發(fā)酵菌MDR-PDR-XDRMDRMulti Drug ResistantPDRPan Drug Resistant(泛耐藥)XDRExtensive Drug Resistant(大量/廣泛/大規(guī)模耐藥)Extreme Drug Resistant(極端/極度耐藥)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當(dāng)今世界主要的MDR 、 XDR 、 PDR1.甲氧西林耐藥金葡菌(MRSA)2.萬古霉素耐藥腸球菌(VRE)和金葡菌(VRSA)3.產(chǎn)超廣譜-內(nèi)酰胺酶(ESBLs) 大腸埃希菌和肺炎克雷伯菌4.高產(chǎn)頭孢菌素酶腸桿菌科細(xì)菌5.多重耐藥

8、耐藥 銅綠假單胞菌和鮑曼不動桿菌多重耐藥菌流行時期感染治療有效性細(xì)菌耐藥性增加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迅速的合理的治療重要嗎？ 產(chǎn)ESBLs的大腸埃希菌、肺炎克雷伯菌和奇異變形桿菌引起的菌血癥21天病死率Tumbarello et al, Antimicrob Agents Chemother 51: 1987 94, 2007定義：首次血培養(yǎng)陽性， 72小時后

10、應(yīng)用體外敏感的抗菌藥物進(jìn)行初次治療。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腸桿菌科細(xì)菌 臨床關(guān)注的主要-內(nèi)酰胺酶超廣譜-內(nèi)酰胺酶(ESBLs)高產(chǎn)頭孢菌素酶(AmpC酶)極少數(shù)菌株產(chǎn)碳青霉烯酶 (碳青霉烯酶KPC)MDRXDR產(chǎn)ESBLs菌株血行感染死亡率顯著增加（Meta分析）產(chǎn)ESBLs菌株與不產(chǎn)ESBLs菌株血行感染死亡率比較的Meta分析包括16個研究產(chǎn)ESBLs菌株菌血癥死亡率顯著增加(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病人伴發(fā)熱感染性疾病非感染性疾病病毒細(xì)菌結(jié)核真菌寄生蟲GG療效好療效不好停藥或降階梯調(diào) 整根據(jù)耐藥狀況經(jīng)驗性

13、治療取相應(yīng)標(biāo)本進(jìn)行病原學(xué)檢測根據(jù)檢測結(jié)果調(diào)整抗生素臨床病情的判定 發(fā)熱（38C）或低溫（36C） 寒戰(zhàn) 白細(xì)胞增多（計數(shù)大于10，000109/L，特別有“核 左移” 未成熟的或桿狀核的白細(xì)胞） 粒細(xì)胞減少（成熟的多核白細(xì)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%產(chǎn)ESBLs菌株血行感染：病死率增加的危險因素之一廣譜頭孢菌素的治療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產(chǎn)ESBLs菌株血行感染：頭孢菌素的經(jīng)驗性治療療效判斷與MIC的相關(guān)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折點？頭孢他啶對產(chǎn)ESBLs菌株MIC分布產(chǎn)ESBLs菌株感染：頭孢菌素的經(jīng)驗性治療療效判斷與MIC的相關(guān)性ESBLs檢測？更改折點臨床病例資料ESBLs檢測的必要性抗菌藥物的選擇 頭孢菌素治療對其敏感的產(chǎn)ESBLs菌株的嚴(yán)重感染仍導(dǎo)致治療的失敗 臨床微生物實驗室指導(dǎo)臨

17、床合理選擇抗菌藥物產(chǎn)ESBLs菌株的嚴(yán)重感染不適合選擇頭孢菌素作為起始經(jīng)驗性治療?。词顾幟籼崾久舾校┊a(chǎn)ESBLs菌株血行感染：不同抗菌藥物經(jīng)驗性治療療效比較氟喹諾酮類部分臨床研究證實環(huán)丙沙星治療產(chǎn)ESBLs菌株感染的有效性但產(chǎn)ESBLs合并對氟喹諾酮類耐藥菌株迅速增加！中國臺灣，20% 的產(chǎn)ESBL肺炎克雷伯菌對環(huán)丙沙星耐藥亞洲其他地區(qū)的產(chǎn)ESBLs菌株環(huán)丙沙星耐藥率很高美國，產(chǎn)ESBLs合并環(huán)丙沙星耐藥菌株的爆發(fā)流行，如1999年15家醫(yī)院中的34肺克產(chǎn)ESBLs，其中僅42對環(huán)丙沙星敏感尤其是中國大陸B(tài)ell 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.產(chǎn)ESBLs菌株血行感染：不同抗菌藥物經(jīng)驗性治療療效比較Clinical

20、 Infectious Diseases 2003; 39:317碳青霉烯類抗生素產(chǎn)ESBLs菌株血行感染：不同抗菌藥物經(jīng)驗性治療療效比較不同抗菌藥物治療方案30天病死率比較 ：Thirty-day mortality rates碳青霉烯類 12.9% (8 of 62)環(huán)丙沙星 10.3% (3 of 29）頭孢菌素 26.9% (7 of 26)氨基糖苷類26.9% (7 of 26)選擇碳青霉烯類抗生素作為產(chǎn)ESBLs菌株感染的經(jīng)驗性治療的合理性！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存活率產(chǎn)ESBLs菌株感染：抗菌藥物的選擇產(chǎn)ESBLs菌株感染：非碳青霉烯類抗生素治療病死率高于碳青霉烯類抗生素頭孢菌素治療與產(chǎn)ESBLs菌株血行感染療效較差頭孢菌素治療對其敏感的產(chǎn)ESBLs菌株的嚴(yán)重感染療效仍差更慎重的選擇碳青霉烯類抗生素作為治療產(chǎn)ESB

22、Ls菌株感染的起始治療的合理性！根據(jù)病人的疾病及病情根據(jù)微生物的耐藥性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產(chǎn)ESBLs菌株感染: 抗菌藥

26、物的選擇Extended-Spectrum -Lactamases: a Clinical UpdateCLINICAL MICROBIOLOGY REVIEWS, Oct. 2005, p. 657686根據(jù)病人的疾病及病情選擇抗菌藥物國內(nèi)ESBLs菌株感染治療1. 嚴(yán)重感染的病人：碳青霉烯類；2. 輕中度的感染：可選擇復(fù)合制劑（舒普深或特治星），應(yīng)用時劑量應(yīng)適當(dāng)加大；療效不佳 時可改碳青霉烯類；3. 頭霉素也可應(yīng)用，但耐藥比國外嚴(yán)重；4. 環(huán)丙沙星85%左右耐藥；阿米卡星50%左右耐藥。Prevalence of ESBLsCHINET surveillance, China, 2005-

27、2008各地區(qū)產(chǎn)ESBL大腸和肺克的檢出率大腸=152株肺克=83株產(chǎn)ESBLs大腸和肺克的耐藥率大腸=152株肺克=83株患者，男性，58歲，因右上腹不適一周伴發(fā)熱五天（頭孢呋辛4天）血常規(guī)：16.2 *10E9/L, N(92%)CRP218mg/L膽石癥，膽道感染敗血癥？何種抗菌藥物？選碳青霉烯類對嗎?肝膿瘍 男性，50歲，臨安人發(fā)熱，白細(xì)胞高，CRP高 B超，CT報告肝膿瘍頭孢曲松和甲硝唑舒普深但白細(xì)胞，CRP仍高B超，CT報告肝膿瘍基本吸收如何處理？如果是腹腔,膽道,泌尿道感染時:經(jīng)驗性治療首先要覆蓋:大腸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