個(gè)體化抗菌治療策略

1、 經(jīng)驗(yàn)性抗感染治療的基本原則 與臨床實(shí)踐 個(gè)體化抗感染治療Case study acute fever既往健康急性發(fā)熱、無(wú)器官系統(tǒng)感染的臨床表現(xiàn)WBC正常阿奇霉素、紅霉素、白霉素、潔霉素.(基層)二代頭孢、三代頭孢、喹諾酮類、酶抑制劑復(fù)合制劑、厄他培南.(大醫(yī)院)感冒樣癥狀輕咳、少痰漸進(jìn)性氣短各種抗菌藥物 -廣譜+聯(lián)合呼吸衰竭慢性咳嗽和黃痰-原因哮喘 后鼻腔鼻漏病毒感染后氣道高反應(yīng)性胃酸返流吸煙相關(guān)的慢性支氣管炎支氣管擴(kuò)張癥彌漫性泛細(xì)支氣管炎肺泡蛋白沉積癥急性發(fā)熱-WBC不高/淋巴增高（無(wú)感染灶）-病毒！-WBC增高/中性粒增高/核左移 -細(xì)菌? 部位/病原體？ 原發(fā)性菌血癥？慢性發(fā)熱-IE、

2、布病、慢性感染灶？結(jié)核病？-非感染性發(fā)熱藥物熱、風(fēng)濕病、惡性腫瘤正確診斷是正確治療的前提發(fā)熱的診斷與鑒別診斷Mortality* Associated With Initial Inadequate Therapy in Critically Ill ICU Patients0%20%40%60%80%100%Luna, 1997Ibrahim, 2000Kollef, 1998Harbarth, 2003Rello, 1997Alvarez-Lerma, 1996Initial adequate therapyInitial inadequate therapy*Mortality refe

3、rs to crude or infection-related mortality.Alvarez-Lerma F et al. Intensive Care Med 1996;22:387-394. Rello J et al. Am J Respir Crit Care Med 1997;156:196-200. Harbarth S et al. Am J Med 2003;115:529-535. Kollef MH et al. Chest 1998;113:412-420. Ibrahim EH at al. Chest 2000;118:146-155. Luna CM et

4、al. Chest 1997;111:676-685. Valles J et al. Chest 2003;123:1615-1624.Mortality*Valles, 2003Inadequate Therapy Was Closely Associated With Antibiotic Resistance% Occurrence of PathogenKollef MH. Clin Infect Dis 2000;31(Suppl 4):S131-S138.充分初始治療改善預(yù)后/不充分治療與耐藥緊密相關(guān) 2001年在歐洲危重病會(huì)議和ICC從“猛擊策略”到“降階梯策略” 開始的廣覆蓋

5、-對(duì)于重癥感染 開始即使用廣譜抗生素以覆蓋所廣譜抗生素以覆蓋所有可能致病菌有可能致病菌隨后的降階梯-48-72小時(shí)后 根據(jù)微生物學(xué)檢查結(jié)果調(diào)整抗生素的使用/使之更有針對(duì)性 目的和意義:防止病情迅速惡化 VSVS 防止細(xì)菌產(chǎn)生耐藥/降低費(fèi)用 “廣覆蓋”與“降階梯”的有機(jī)統(tǒng)一 對(duì)VAP最初治療應(yīng)針對(duì)G-和G+包括MRSA，Gram涂片發(fā)現(xiàn)G+球菌與培養(yǎng)金葡萄陽(yáng)性率之間高度一致。故涂片見G+菌應(yīng)加用萬(wàn)古霉素代表方案-泰能萬(wàn)古48歲、男性、同種異體腎移植術(shù)后3.5個(gè)月13天前出現(xiàn)發(fā)熱（T 38.9），繼之咳嗽/無(wú)痰、進(jìn)行性氣短胸片先后:頭孢呋辛(3d)、莫西沙星(3d)、哌拉西林/他唑巴坦(3d)、亞

6、胺培南/西司他丁萬(wàn)古霉素(3d)查體:發(fā)紺、RR 24/分、P 118/分、雙肺未聞及干濕羅音ABG:PH 7.48、PO2 56mmHg、PCO2 30mmHgCase study-PCP 58歲、男性、既往身體健康11天前出現(xiàn)發(fā)熱（T 38.7），繼之咳嗽，少痰；胸片(見右)先后頭孢唑林(3d)、哌拉西林/他唑巴坦(3d)，無(wú)效病情繼續(xù)加重，呼吸衰竭ALT/AST/Bilirubins/LDH/CK-MBUrinalysis-pro (+) WBC/RBC /CAST(+)再次胸片(見右)換用碳青酶烯抗MRSA抗真菌無(wú)效，呼吸衰竭，轉(zhuǎn)診Case study-LD 58歲、女性、自述既往身體

7、“健康”1天前突然出現(xiàn)上消化道出血診斷:肝炎后肝硬化，食道靜脈曲張出血急診行門脈斷流手術(shù)術(shù)后第二天出現(xiàn)發(fā)熱（T 38.9），繼之咳嗽、咳痰，胸片(見右)血?dú)夥治?PaO2=56mmHg（吸空氣）碳青酶烯+抗MRSA+抗真菌臨床轉(zhuǎn)歸 -呼吸衰竭好轉(zhuǎn)，下一步？Case study-POP 問(wèn)題在哪里？經(jīng)驗(yàn)性抗感染治療的基本原則與臨床實(shí)踐Rapid testsWhen available. Gram stain! Start adequate antibiotic coverage(within 1 hour?)Drain purulent collectionSamplingIncluding i

8、nvasive procedureswhen needed (BAL)經(jīng)驗(yàn)性治療和目標(biāo)治療的統(tǒng)一留取標(biāo)本進(jìn)行微生物學(xué)檢查開始經(jīng)驗(yàn)性抗感染治療目標(biāo)治療選擇哪種抗菌藥物(which antibiotic?) 感染部位的常見病原學(xué)(possible pathogens on site of infection) 選擇能夠覆蓋病原體的抗感染藥物(antibiotics requirement) -抗菌譜/組織穿透性/耐藥性/安全性/費(fèi)用考慮藥代動(dòng)力學(xué)/藥效動(dòng)力學(xué)(PK/PD)考慮病人生理和病理生理狀態(tài)( physiologic and pathophysiology) 高齡/兒童/孕婦/哺乳(adva

9、nced age/children/pregnant women/breast feeding) 腎功能不全/肝功能不全/肝腎功能聯(lián)合不全(renal/heptic dysfunction/combined)其它因素(other considerations) 殺菌和抑菌/單藥和聯(lián)合/靜脈和口服/療程 (cidal vs static/ mono vs combination/ IV vs PO/ duration)經(jīng)驗(yàn)性抗感染治療藥物選擇-considerations in choosing antibiotic for empiric therapy l培養(yǎng)結(jié)果前依據(jù)基本信息選擇抗感染藥物

10、 choosing Abx before culture result感染部位和可能病原體的關(guān)系 association of pathogen with site of infectionGram染色結(jié)果-與上述病原體是否符合？ Gram stain-in accordance with suspected pathogen?l某些病原體易于造成某些部位的感染 Some pathogen easily cause some site of infection 經(jīng)驗(yàn)性抗感染治療藥物選擇-considerations in choosing antibiotic for empiric ther

11、apy 不同感染部位的常見感染性病原體Possible pathogens on site of infectionM outh Peptococcus Peptostreptococcus Actinom yces Skin/Soft T issue S. aureus S. pyogenes S. epiderm idis Pasteurella B one and Joint S. aureus S. epiderm idis Streptococci N . gonorrhoeae G ram -negative rods A bdom en E. coli, Proteus K le

12、bsiella Enterococcus Bacteroides sp. U rinary Tract E. coli, Proteus K lebsiella Enterococcus Staph saprophyticus U pper R espiratory S. pneum oniae H . influenzae M . catarrhalis S. pyogenes Low er R espiratory C om m unity S. pneum oniae H . influenzae K . pneum oniae Legionella pneum ophila M yco

13、plasm a, Chlam ydia Low er R espiratory H ospital K . pneum oniae P. aeruginosa Enterobacter sp. Serratia sp. S. aureus M eningitis S. pneum oniae N . m eningitidis H . influenza G roup B Strep E. coli Listeria 注意特殊修正因子/特別是先期抗菌藥物對(duì)細(xì)菌學(xué)的影響 不同感染部位的常見感染性病原體Possible pathogens on site of infection關(guān)注特殊病原體肺孢

14、子菌肺炎 -免疫缺陷 -相對(duì)特異臨床 -積極病原學(xué)檢查重癥軍團(tuán)菌肺炎發(fā)熱、少痰多肺葉、多肺段受累肺外表現(xiàn)抗菌譜(coverage)組織穿透性(tissue penetration)耐藥性(resistance, specifically local resistance) 參考代表性資料/依靠當(dāng)?shù)刭Y料安全性(safety profile) 藥物本身/制劑/工藝/雜質(zhì)費(fèi)用/效益(cost/effectiveness) 失敗或副作用致再治療費(fèi)用更高經(jīng)驗(yàn)性抗感染治療藥物選擇的基本原則評(píng)價(jià)病原體耐藥可能？是否耐藥菌？ -了解耐藥病原體流行狀況 參考代表性治療/依靠當(dāng)?shù)刭Y料 -個(gè)體化用藥 病人來(lái)源：社區(qū)

15、、養(yǎng)老院、醫(yī)院 高齡、基礎(chǔ)疾病、近期抗菌藥物、近期住院、侵襲性操作、晚發(fā)醫(yī)院感染 S. aureusPenicillin1944Penicillin-resistantS. aureus金黃色葡萄球菌耐藥的發(fā)生發(fā)展過(guò)程金黃色葡萄球菌耐藥的發(fā)生發(fā)展過(guò)程Methicillin1962Methicillin-resistantS. aureus (MRSA)Vancomycin-resistantenterococci (VRE)Vancomycin1990s1997VancomycinintermediateS. aureus(VISA)2002Vancomycin-resistantS. aur

16、eusCDC, MMWR 2002;51(26):565-5671960評(píng)價(jià)病原體耐藥可能？是否耐藥菌？ -了解耐藥病原體流行狀況 參考代表性治療/依靠當(dāng)?shù)刭Y料 -個(gè)體化用藥 病人來(lái)源：社區(qū)、養(yǎng)老院、醫(yī)院 高齡、基礎(chǔ)疾病、近期抗菌藥物、近期住院、侵襲性操作、晚發(fā)醫(yī)院感染 % Wang H, Chen M. Diagnos Microbiol Infect Dis, 2005, 51, 201-208CMSS/SEANIR/CARES. year細(xì)菌耐藥監(jiān)測(cè)結(jié)果如何解讀？細(xì)菌耐藥監(jiān)測(cè)結(jié)果如何解讀？2002-2004: SMART - ESBL in community in China20022

17、0032004E. coli48h21/5936%47/7860%48/8259%Klebsiella48r12/3238%12/3336%18/3551%Study done in referral tertiary university hospitals in ChinaPrevious antibiotic exposure may select more ESLB-producerSMART China might overestimate ESBL prevalence in China實(shí)驗(yàn)室藥物敏感性監(jiān)測(cè)的意義及缺陷實(shí)驗(yàn)室藥物敏感性監(jiān)測(cè)的意義及缺陷意義-反映了耐藥趨勢(shì)/告誡我們要

18、慎重使用抗菌藥物 -在制定用藥方案時(shí)考慮耐藥性導(dǎo)致的治療失敗缺陷 -實(shí)驗(yàn)室收集到的菌株/大型教學(xué)醫(yī)院/ICU 抗生素選擇壓力導(dǎo)致耐藥性高估！ -沒有臨床背景資料/不利用于個(gè)體化用藥 (年齡、基礎(chǔ)疾病、社區(qū)/醫(yī)院感染、前期抗菌藥物使用) Prevalence of rectal carriage of Extended-Spectrum -lactamase-producing Escherichia Coli among elderly people in a community setting in Shenyang Cross sectional study-276 elderly、rec

19、tal swab/E coli isolation/ESBL screening、genotyping and PEGFResult: prevalence of ESBL positive E Coli 7.0%（19/270） CTX-M type -CTX-M-14 63.2%, other:CTX-M-22 and CTX-M-24， 2 CTX-M-57-like -GA substitution in 865 point leading to DN subsitution in 289 point in AA ( new, sequence No.EF426798) Tian SF

20、, Chen BY.Prevalence of rectal carriage of Extended-Spectrum -lactamase -producing Escherichia Coli among elderly people in a community setting in Shenyang, China. Canadian Journal of microbiology 2008;54:15評(píng)價(jià)病原體耐藥可能？是否耐藥菌？ -了解耐藥病原體流行狀況 參考代表性治療/依靠當(dāng)?shù)刭Y料 -個(gè)體化用藥-合理用藥的核心 病人來(lái)源：社區(qū)、養(yǎng)老院、醫(yī)院 高齡、基礎(chǔ)疾病、近期抗菌藥物、近期住

21、院、侵襲性操作、晚發(fā)醫(yī)院感染 Risk factors for infection with ESBL producers (MDR) outside hospitalFactorOdds ratioRx 3 gen ceph15.8Rx 2 gen ceph10.1Hospital in last 3 months8.95Rx quinolone4.1Rx penicillins4.0Antibiotic Rx in last 3 months3.23Age 60 years2.65Diabetes2.57Colodner et al EJCMID 2004 23, 163.Univaria

22、te analysis of risk factors for carriage of ESBL-producing Escherichia coli in the community (n=270)Potential Risk factors No(%) ESBLs Total No Odds ratio(95% CI) P value Age (years) 74 16(7.4) 216 75 3(5.6) 54 0.74(0.21-2.62) 0.77 Gender Female 12(7.8) 153 Male 7(6.0) 117 0.81 (0.31-2.13) 0.81 Diab

23、etes No 11(6.3) 174 Yes 8(8.3) 96 1.35(0.52-3.47) 0.62 Hospitalization in past one year No 18(6.8) 264 Yes 1(16.7) 6 2.73(0.30-24.66) 0.34 Surgery in past one year No 19(7.1) 268 Yes 0(0) 2 0.0 0.8 Use of antibiotic in past three months No 12(5.3) 227 Yes 7(16.3) 43 3.48(1.29-9.44) .018 醫(yī)院感染醫(yī)院感染- -產(chǎn)

24、產(chǎn)ESBL 細(xì)菌感染的危險(xiǎn)因素細(xì)菌感染的危險(xiǎn)因素Prospective study of 455 episodes of K. pneumoniae bacteremia (253 nosocomial) in 12 hospitalsn30.8% 為醫(yī)院獲得, ICU中43.5%產(chǎn)ESBLsnESBLs危險(xiǎn)因素 -先期使用氧亞氨基-內(nèi)酰胺類抗菌藥物 -過(guò)去14天內(nèi)使用2 d (OR= 3.9). n其它危險(xiǎn)因素 TPN, 腎功衰竭,燒傷n非ESBL危險(xiǎn):碳青霉烯、頭孢吡肟、喹諾酮、氨基糖苷類 Paterson et al: Ann Intern Med 2004; 140:26-32.VAP

25、耐藥菌感染的危險(xiǎn)因素耐藥菌感染的危險(xiǎn)因素135 次VAP ICU變量 OR PMV7 days 6.0 .009先期ABs 13.5 7 days / prior ABsTrouillet, et al. Am J Respir Crit Care Med. 1998;157:531No Risk Factors for MDR PathogensRisk Factors for MDR EnterobacteriaceaeaRisk Factors for MDR PseudomonasHealth care contact No Yes! (eg, recent hospital admi

26、ssion, nursing home, dialysis) without invasive procedure Yes, Long hospitalization and/or infection following invasive procedures (5 days) Recent Abx No Yes! (14 days in past 90 days) Yes ! (14 days in past 90 days) Patient characteristics Young few comorbidities 65 yrs comorbidities such as TPN or

27、 renal insufficiency co-morbidities such as CF, structural lung disease, advanced AIDS, neutropenia, or other severe immunodeficiency aExcept nonfermenters/non-Pseudomonas species.Adapted from Carmeli Y. Predictive factors for multidrug-resistant organisms. In: Role of Ertapenem in the Era of Antimi

28、crobial Resistance newsletter. Available at: www.invanz.co.il/secure/downloads/IVZ_Carmeli_NL_2006_W-226364-NL.pdf. Accessed 7 April 2008; Dimopoulos G, Falagas ME. Eur Infect Dis. 2007;4951; Ben-Ami R, et al. Clin Infect Dis. 2006;42(7):925934; Pop-Vicas AE, DAgata EMC. Clin Infect Dis. 2005;40(12)

29、:17921798; Shah PM. Clin Microbiol Infect. 2008;14(suppl 1):175180.Stratification for Risk for MDR Gram-Negative PathogensEpidemiology of MRSAH-MRSAReservoires -hospitals -LTCFs5 genetic backgroudsH-MRSA in community -patients with risk factors -contact with patients with risk factorsTrue community-

30、MRSA -no healthcare-associated risk factors -with PVL geneshealthcarecommunityAcquiredOnsetH-MRSA 感染危險(xiǎn)因素: 年齡65歲， 嚴(yán)重基礎(chǔ)疾病， 傷口 廣譜抗生素使用， 住院時(shí)間延長(zhǎng)， 多次住院 侵襲性操作（氣管插管、切開/植入血管導(dǎo)管）合理使用抗MRSA藥物糖肽類/利奈唑胺重癥感染耐藥菌感染！重癥感染革蘭陰性腸桿菌科細(xì)菌感染！ PCP、軍團(tuán)菌、肺炎鏈球菌都可致重癥感染是否重癥? -依據(jù)臨床表現(xiàn)/器官功能狀態(tài) -氧和、血液動(dòng)力學(xué)、腎功能 腸功能PCPLD為什么隨意使用廣譜抗菌藥物和聯(lián)合使用？ SIR

31、S plus Documented 重癥感染的臨床判定Severe Sepsis Sepsis plus Septic shock Severe sepsis and Despite adequate ressucitationat least 2 of the followingsT 38or 90 beats/ minRR 20 breaths/minWBC 12,000 cells/ml, 10% immature formsACCP/SCCM consensus conference 1992重癥感染的臨床判定宿主因素-Host factorn免疫缺陷u高齡、疾病、治療感染所致臨床綜合

32、征n中樞神經(jīng)系統(tǒng)-CNSn醫(yī)院獲得性肺炎-HAPu呼吸機(jī)相關(guān)肺炎-VAPn菌血癥-Bacteremiau肺炎-pneumoniau原發(fā)性或不明原因-Primary or unknownn嚴(yán)重軟組織感染-Severe soft tissue infection病原體致病性/耐藥性 High virulence or resistanceu金黃色葡萄球菌-S. aureusu銅綠假單孢菌-P. aeruginosau化膿性鏈球菌-S. pyogenes獲得感染得場(chǎng)所-Nosocomial infectionsu病人因素-Patient factors免疫缺陷-Immunocompromized病情

33、危重-Critically illu病原體因素-Pathogen factors高致病性和/或難治性微生物 Virulent and / or difficult to treat organismsPCPLD耐藥菌感染 VS 嚴(yán)重感染-PCP和LD告訴我們什么？觀點(diǎn): 耐藥性判斷 對(duì)于合理選擇 抗菌藥物更重要！ 包括重癥感染選擇哪種抗菌藥物(which antibiotic?) 感染部位的常見病原學(xué)(possible pathogens on site of infection) 選擇能夠覆蓋病原體的抗感染藥物(antibiotics requirement) -抗菌譜/組織穿透性/耐藥性/

34、安全性/費(fèi)用考慮藥代動(dòng)力學(xué)/藥效動(dòng)力學(xué)(PK/PD)考慮病人生理和病理生理狀態(tài)( physiologic and pathophysiology) 高齡/兒童/孕婦/哺乳(advanced age/children/pregnant women/breast feeding) 腎功能不全/肝功能不全/肝腎功能聯(lián)合不全(renal/heptic dysfunction/combined)其它因素(other considerations) 殺菌和抑菌/單藥和聯(lián)合/靜脈和口服/療程 (cidal vs static/ mono vs combination/ IV vs PO/ duration)

35、經(jīng)驗(yàn)性抗感染治療合理選擇藥物-considerations in choosing antibiotic for empiric therapy 評(píng)估病原體 有的而放矢！評(píng)估耐藥性 到位不越位！評(píng)估嚴(yán)重性 廣譜 VS 窄譜？ 單藥 VS 聯(lián)合？選擇哪種抗菌藥物(which antibiotic?) 感染部位的常見病原學(xué)(possible pathogens on site of infection) 選擇能夠覆蓋病原體的抗感染藥物(antibiotics requirement) -抗菌譜/組織穿透性/耐藥性/安全性/費(fèi)用考慮藥代動(dòng)力學(xué)/藥效動(dòng)力學(xué)(PK/PD)考慮病人生理和病理生理狀態(tài)( p

36、hysiologic and pathophysiology) 高齡/兒童/孕婦/哺乳(advanced age/children/pregnant women/breast feeding) 腎功能不全/肝功能不全/肝腎功能聯(lián)合不全(renal/heptic dysfunction/combined)其它因素(other considerations) 殺菌和抑菌/單藥和聯(lián)合/靜脈和口服/療程 (cidal vs static/ mono vs combination/ IV vs PO/ duration)經(jīng)驗(yàn)性抗感染治療藥物選擇-considerations in choosing an

37、tibiotic for empiric therapy 聯(lián)合用藥的理由補(bǔ)充單一用藥的抗菌譜不足！補(bǔ)充單一用藥的抗菌譜不足！協(xié)同作用如銅綠假單孢菌菌血癥協(xié)同作用如銅綠假單孢菌菌血癥減少耐藥？減少耐藥？2007 ATS/IDSA Guidelines: InpatientsMandell LA, et al. Clin Infect Dis 2007CAP Inpatient TherapyMedical WardIntensive Care UnitRecentAntibioticNo RecentAntibioticRespiratory FQ alone ORAdvanced macrol

38、ide + -lactamNo Pseudomonas RiskNo -lactam Allergy-lactam Allergy-lactam + advanced macrolide OR + respiratory FQ* Regimen depend on nature of recent Abx therapyRespiratory FQ + aztreonamPseudomonas RiskNo -lactam Allergy-lactam Allergy Anti-pseudomonal, antipneumococcal b- lactam /penem + Cipro/Levo 750 OR Anti-pseudomonal, antipneumococcal b- lactam /penem + aminoglycoside + Azithromycin Aztreonam + respiratory FQ + aminoglycosideAdvanced m