pct臨床應(yīng)用指導(dǎo)抗生素治療

1、PCT臨床應(yīng)用—指導(dǎo)抗生素治療,浙江省人民醫(yī)院ICU 孫仁華,內(nèi)容,PCT特點(diǎn)、應(yīng)用指導(dǎo)抗生素治療,PCT,PCT是降鈣素?zé)o激素活性的前肽物質(zhì)，116個(gè)氨基酸組成的糖蛋白，分子質(zhì)量約13 ku，由甲狀腺C細(xì)胞合成 ，生理情況下血濃度<0.1 ng/mL。嚴(yán)重細(xì)菌、真菌和寄生蟲感染且有全身表現(xiàn)時(shí)，血清PCT含量升高,不受激素應(yīng)用的影響。3-6小時(shí)即可檢測(cè)到，8-24小時(shí)達(dá)高峰，半衰期20-24小時(shí)。病毒感染或非感染性致病原炎

2、癥反應(yīng)(SIRS)，PCT含量不升高或僅輕中度升高,非特異性PCT誘因-可能的假陽(yáng)性結(jié)果包括:手術(shù)創(chuàng)傷、多處創(chuàng)傷：在手術(shù)后的前兩天出生48小時(shí)以內(nèi)的新生兒免疫刺激藥物 (OKT3,TNFa,IL-2.)嚴(yán)重?zé)齻和肝鲋惺?PCT略微增加感染早期 (? 6-12 小時(shí)后重新檢測(cè)!)之前進(jìn)行過(guò)有效的抗生素治療非典型性肺炎(肺炎支原體、肺炎衣原體)局部感染,PCT的局限性,PCT的影響因素,受以下因素影響 * 甲狀腺功

3、能 是功能性甲狀腺髓樣癌的腫瘤標(biāo)志物* 腎功能 嚴(yán)重腎功能受損者中水平較高不受以下因素影響* 類固醇藥物* 自身免疫性疾病* 年齡、性別* 免疫功能低下狀態(tài):肝硬化、HIV感染,PCT的應(yīng)用,診斷、鑒別診斷細(xì)菌感染判斷感染的嚴(yán)重程度及預(yù)后指導(dǎo)抗生素的治療,PCT與真菌感染,Candida (念珠菌) 念珠菌相關(guān)的膿毒癥并沒有顯現(xiàn)出一致性的上升Aspergillosis (曲霉菌)

4、 PCT 會(huì)延遲上升 第一天 平均 1.5 ng/ml,重癥醫(yī)學(xué)雜志.2006;32:1577-83,菌血癥,念珠菌血癥,其他病原體感染中的PCT水平,在一次內(nèi)毒素刺激的人體試驗(yàn)中不同的生物標(biāo)志物的動(dòng)力學(xué)變化,Reinhart K, et al. Crit Care Clin 2006;22;503-519,在監(jiān)測(cè)方面，PCT有著明顯的優(yōu)勢(shì)!,PCT與其他炎癥反應(yīng)因子,在對(duì)感染程度嚴(yán)重性的判斷上，PCT比IL

5、-6、IL-8能更好的區(qū)分膿毒癥、嚴(yán)重膿毒癥、膿毒性休克，有著更好的分析效果,Impact of guiding ATB duration by PCT levels on ATB consumption in pts with severe sepsis and no proven source and pathogen.,在膿毒癥患者進(jìn)入ICU當(dāng)天，進(jìn)行血清降鈣素原（PCT）、白介素6（IL-6）和白介素8（IL-8）的檢測(cè)結(jié)果進(jìn)行

6、的比較分析Use of Procalcitonin level as part of a decision tree to discontinue antibiotics when started empirically in the ICU in hemodynamically stable patients with no site of infection identified,All kind of hospitalized

7、 patients12 studies,AUC PCT > AUC CRP (p < 0.05),PCT 集合的靈敏度：88％ 集合的特異性：81％CRP 集合的靈敏度：75％ 集合的特異性：67％,PCT與其他炎癥反應(yīng)因子,PCT,IL-6,CRP,PCT比傳統(tǒng)的CRP、IL-6等炎性指標(biāo)，有著更好的ROC曲線下分布面積，體現(xiàn)出更具優(yōu)勢(shì)的診斷靈敏度和特異性,Müller

8、et al., CCM 2000,lactates,Muller et al.,Circulation 2004,在感染性心內(nèi)膜炎的早期診斷上，PCT體現(xiàn)出比CRP更好的診斷靈敏度和特異性,1-,細(xì)菌感染嚴(yán)重程度判斷,在感染疾病的發(fā)展過(guò)程中，PCT隨著嚴(yán)重程度的不同（局部感染、膿毒血癥、嚴(yán)重膿毒血癥、膿毒性休克），呈現(xiàn)由低到高的濃度變化,PCT血中濃度與病程發(fā)展呈正相關(guān)對(duì)于感染程度及器官機(jī)能障礙的嚴(yán)重性進(jìn)行準(zhǔn)確的判斷,E.J. Gia

9、marellos-Bourboulis et al.,Jan 07 ... Sept. 2008 ....,Mortality Rate in Patients with Sepsis....(The Hellenic Sepsis Study Group) Outside ICU: - PCT 0.12 ng/ml: Mortality rate 19.5%Inside ICU: - PC

10、T 0.53 ng/ml: Mortality rate 45.1%,報(bào)警值: 所有數(shù)值 > 1.0ng/ml, 從第一天高于 1.0ng/ml時(shí)開始計(jì)算非報(bào)警值:從第一天高于 1.0ng/ml時(shí)開始減少,并以后數(shù)值均 1.0ng),Jensen et al., Crit Care Med, 2006,PCT濃度變化與ICU膿毒癥患者生存率的關(guān)系,,指導(dǎo)抗生素治療,是否需要抗生素處方？評(píng)估抗生素治療成功與否？什

11、么時(shí)候?？股??,抗生素治療每延遲1小時(shí)，死亡率上升7%,Kumar et al., CCM 2006,D. Antimicrobial Therapy,We recommend that intravenous antimicrobial therapy be started as early as possible and within the first hour of recognition of septic shock (

12、grade 1B) and severe sepsis without septic shock (grade 1C). Appropriate cultures should be obtained before initiating antibiotic therapy but should not prevent prompt administration of antimicrobial therapy,D. Antimicro

13、bial Therapy,We suggest the use of low procalcitonin levels or similar biomarkers might be useful to assist the clinician in the discontinuation of empiric antibiotics in patients who appeared septic, but have no subsequ

14、ent evidence of infection (grade 2C).,Thirty-three studies fulfilled inclusion criteria (3,943 patients, 1,828 males, 922 females; mean age: 56.1 yrs;1,825 patients with sepsis, severe sepsis, or septic shock; 1,545 with

15、 only systemic inflammatory response syndrome); eight studies could not be analyzed statistically. Global mortality rate was 29.3%,Global odds ratios for diagnosis of infection complicated by systemic inflammation were 1

16、5.7 for the 25 studies (2,966 patients) using procalcitonin (95% confidence interval, 9.1–27.1) and 5.4 for the 15 studies (1,322 patients) using C-reactive protein (95% confidence interval, 3.2–9.2).,Crit Care Med 2006;

17、 34:1996–2003,Global diagnostic accuracy odds ratios for procalcitonin (PCT, circle, solid line) and C-reactiveprotein (CRP, triangle, dashed line); n 15 studies. OR, odds ratio; CI, confidence interval.,Summary receiv

18、er operating characteristics curves for procalcitonin (circle, solid line) and Creactive protein (triangle, dashed line), accordingto Moses and Littenberg model; n 15 studies,Lancet 2004; 363, 600-607,研究背景：在西方國(guó)家，下呼吸道感

19、染(LRTI)是應(yīng)用抗生素最常見的指征目前臨床癥狀、體征以及常用的實(shí)驗(yàn)室檢查，均無(wú)法準(zhǔn)確分辨LRTI的病原體(細(xì)菌?病毒?) ，因此約75%的患者接受抗生素的治療，盡管有時(shí)候是病毒感染針對(duì)細(xì)菌感染，PCT是一個(gè)敏感性較高的生物學(xué)指標(biāo)，它在一定程度上可以協(xié)助臨床內(nèi)科醫(yī)師管理抗生素的使用,研究病例組成,標(biāo)準(zhǔn)組PCT指導(dǎo)組 Good clinical outcome 好的臨床效果

20、 97% 97%ATB prescribed 抗生素用率 83% 44%Duration of ATB treatment (d) 抗生素治療天數(shù) 12.8 10.9ATB cost per patients (US$) 抗生素成本 202.5 96.3,,兩組臨床結(jié)果比較,兩組抗

21、生素使用率比較,抗生素的使用及成本減少～50％（83％－44％）,p = 0.03,p = 0.003,p < 0.001,p < 0.001,p = 0.003,針對(duì)社區(qū)獲得性肺炎（CAP）患者PCT指導(dǎo)臨床抗生素的使用,如何確定何時(shí)停用抗生素的困難:*多達(dá) 40% 的CAP病人不出現(xiàn)發(fā)熱*>70%推測(cè)為細(xì)菌感染的CAP 病人鑒定不出致病細(xì)菌,結(jié)果表明：使用PCT指導(dǎo)抗生素的使用,其用藥療程由12天降至5天，縮

22、短約 ～55％，但其治療效果不變,n=151 (標(biāo)準(zhǔn)組), n=151 PCT 指導(dǎo)組PCT 指導(dǎo)下，在病人到達(dá)醫(yī)院當(dāng)天，抗生素使用減少14%， (99% Vs 85%), 在整個(gè)療程中，PCT指導(dǎo)組的療程時(shí)間為5天，標(biāo)準(zhǔn)組為12 天兩組的治療結(jié)果相約 : 整體為 83%,減少抗生素的消耗，縮短治療天數(shù),Christ-Crain M et al. Am J Respir Crit Care Med. 2006 Apr 7,PC

23、T指導(dǎo)ICU患者的抗生素治療,Hochreiter et al., Anaesthesist 2008;57:571-577,標(biāo)準(zhǔn): 如果臨床感染的癥狀和體征改善- 并且PCT ≤ 1 ng/ml- 或者3天后PCT下降超過(guò)初始值 25-35% (>1ng/ml)= 建議結(jié)束抗生素治療,Hochreiter et al., Anaesthesist 2008;57:571-577,抗生素治療時(shí)間:

24、 - PCT組：5.9 ± 1.7 d- 對(duì)照組：7.9 ± 0.5 d =無(wú)明顯副作用.,,5-8天就足夠了嗎？,PCT指導(dǎo)ICU患者的抗生素治療,Nobre et al, Am J Respir Crit Care Med. 2008;177(5):498-505,PCT指導(dǎo)抗生素治療,Schuetz P et al, JAMA. 2009;302 (10):1059-1066,目的：監(jiān)測(cè)

25、血清PCT水平是否能在不增加嚴(yán)重并發(fā)癥風(fēng)險(xiǎn)的情況下,最大程度地減少濫用抗生素對(duì)象：2006年10月-2008年3月瑞士6家醫(yī)院的1359例嚴(yán)重LRTI患者設(shè)計(jì)：該研究是一項(xiàng)多中心、非劣性、隨機(jī)控制研究將入選患者隨機(jī)分為對(duì)照組和PCT指導(dǎo)治療組(PCT組)對(duì)照組根據(jù)標(biāo)準(zhǔn)指南確定的抗生素治療方案，PCT組則同時(shí)參考血清PCT水平終點(diǎn)：死亡、入ICU、發(fā)生并發(fā)癥以及30天內(nèi)復(fù)發(fā)感染需要抗生素治療,入選患者流程圖,Phillip

26、 Schuetz, et al. JAMA, 2009(302)10:1059-1066,PCT組與對(duì)照組抗生素使用比較,PCT組抗生素使用時(shí)間低于對(duì)照組,PCT組的總體抗生素使用水平比對(duì)照組平均低25.7%~38.7%,研究后列入時(shí)間(天),Phillip Schuetz, et al. JAMA, 2009(302)10:1059-1066,Primary outcomes included the duration of anti

27、biotic therapy for the first episode of infection and 28-day mortality. Secondary outcomes included length of ICU stay, length of hospitalisation, antibiotic-free days within the first 28 days of hospitalisation, recurr

28、ences, and superinfections,2,199 patients were included in the trials, of which 1,098 were assigned to thePCT-guided treatment arm and 1,101 were assigned to the control group.,antibiotics were discontinued when PCT was

29、 lower than a value that ranged from 0.5 to 1 ng/ml.,. Intensive Care Med 2012,Duration of antibiotic therapy for the first episode of infection was reduced in favour of PCT-guided treatment [pooled weighted mean differe

30、nce (WMD) = -3.15 days, random effects model, 95 % confidence interval (CI) -4.36 to -1.95, P<0.001].,Matthaiou DK et al. Intensive Care Med 2012,Matthaiou DK et al. Intensive Care Med 2012,Matthaiou DK et al. Intensi

31、ve Care Med 2012,Matthaiou DK et al. Intensive Care Med 2012,Secondary outcomes,The length of ICU stay were provided in six out of seven of the included RCTs . There was no difference in length of ICU stayThe length of

32、hospitalisation were provided in three of seven of the included RCTs . There was no difference in length of hospitalisation,Secondary outcomes,Antibiotic-free days within the first 28 days of hospitalisation were provide

33、d in three out of seven of the included RCTs . There was an increase in antibiotic-free days within the first 28 days of hospitalisation in favour of the PCT-guided treatment arm with a pooled WMD of 3.08 days (P = 0.71,

34、 I2 = 0 %, FEM: 95 % CI 2.06–4.10, P<0.001).,Secondary outcomes,Recurrences were provided in three of seven of the included RCTs . There was no difference in recurrencesSuperinfections were provided in three out of s

35、even of the included RCTs . There was no difference in superinfections,膿毒癥患者抗生素有治療效果判斷,(n=109),F. Stüber, University Bonn, Lecture at ISICEM, Brussels 2001,通過(guò)PCT濃度的變化，提示抗生素治療的成功與否,隨著患者對(duì)抗生素治療的響應(yīng)，引起了PCT血中濃度水平的典型變化過(guò)程,持

36、續(xù)升高的PCT水平，提示比較差的預(yù)后（程度加重，死亡）,連續(xù)的監(jiān)測(cè)PCT血中濃度 可以更好的評(píng)估患者的預(yù)后,嚴(yán)重外傷導(dǎo)致膿毒血癥患者，生存者,PCT呈快速下降趨勢(shì)，預(yù)示著成功的治療效果（感染控制、存活）,連續(xù)的監(jiān)測(cè)PCT血中濃度 可以更好的評(píng)估患者的預(yù)后,臨床應(yīng)用,如果PCT非常低： 嚴(yán)重細(xì)菌感染的可能性不大 抗生素應(yīng)用是有問題的 (<0.1ng/ml, <0.3ng/ml)

37、PCT越高 越有可能是敗血癥 越有抗生素應(yīng)用的指正如果PCT下降，炎癥控制； 如果不是，炎癥繼續(xù),建議第3天:“更改或不更改抗生素”如果PCT下降: 不更改抗生素治療！如果PCT 不下降: 更改抗生素治療 !,建議第5天到第7天：第7天抗生素選擇的基本原則：“要么停止，要么更改！”1.停止治療 - 感染的臨床體征消失- PCT顯著下降或低于0.1 ng/ml. 2. 更改抗生素療法

38、- 如果PCT沒有下降（PCT > 0.5 ng/ml 或 > 60% ）- 臨床資料顯示有感染跡象殘留- 如果病人有高風(fēng)險(xiǎn)（免疫抑制，... ...）,PCTbest performing biomarker for bacterial infection/sepsis,細(xì)菌感染后快速升高,細(xì)菌感染時(shí)高的靈敏度和特異性,感染的嚴(yán)重程度,快速反映抗生素的治療效果,,,,,總結(jié),早期診斷,改善細(xì)菌感染/膿