pct臨床應用指導抗生素治療

1、PCT臨床應用—指導抗生素治療,浙江省人民醫(yī)院ICU 孫仁華,內(nèi)容,PCT特點、應用指導抗生素治療,PCT,PCT是降鈣素無激素活性的前肽物質(zhì)，116個氨基酸組成的糖蛋白，分子質(zhì)量約13 ku，由甲狀腺C細胞合成 ，生理情況下血濃度<0.1 ng/mL。嚴重細菌、真菌和寄生蟲感染且有全身表現(xiàn)時，血清PCT含量升高,不受激素應用的影響。3-6小時即可檢測到，8-24小時達高峰，半衰期20-24小時。病毒感染或非感染性致病原炎

2、癥反應(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小時以內(nèi)的新生兒免疫刺激藥物 (OKT3,TNFa,IL-2.)嚴重燒傷血液透析中暑,PCT略微增加感染早期 (? 6-12 小時后重新檢測!)之前進行過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志物* 腎功能 嚴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的應用,診斷、鑒別診斷細菌感染判斷感染的嚴重程度及預后指導抗生素的治療,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 會延遲上升 第一天 平均 1.5 ng/ml,重癥醫(yī)學雜志.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中不同的生物標志物的動力學變化,Reinhart K, et al. Crit Care Clin 2006;22;503-519,在監(jiān)測方面，PCT有著明顯的優(yōu)勢!,PCT與其他炎癥反應因子,在對感染程度嚴重性的判斷上，PCT比IL

5、-6、IL-8能更好的區(qū)分膿毒癥、嚴重膿毒癥、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.,在膿毒癥患者進入ICU當天，進行血清降鈣素原（PCT）、白介素6（IL-6）和白介素8（IL-8）的檢測結(jié)果進行

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與其他炎癥反應因子,PCT,IL-6,CRP,PCT比傳統(tǒng)的CRP、IL-6等炎性指標，有著更好的ROC曲線下分布面積，體現(xiàn)出更具優(yōu)勢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-,細菌感染嚴重程度判斷,在感染疾病的發(fā)展過程中，PCT隨著嚴重程度的不同（局部感染、膿毒血癥、嚴重膿毒血癥、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)對于感染程度及器官機能障礙的嚴重性進行準確的判斷,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%,報警值: 所有數(shù)值 > 1.0ng/ml, 從第一天高于 1.0ng/ml時開始計算非報警值:從第一天高于 1.0ng/ml時開始減少,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,,指導抗生素治療,是否需要抗生素處方？評估抗生素治療成功與否？什

11、么時候?？股??,抗生素治療每延遲1小時，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：在西方國家，下呼吸道感

19、染(LRTI)是應用抗生素最常見的指征目前臨床癥狀、體征以及常用的實驗室檢查，均無法準確分辨LRTI的病原體(細菌?病毒?) ，因此約75%的患者接受抗生素的治療，盡管有時候是病毒感染針對細菌感染，PCT是一個敏感性較高的生物學指標，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,標準組PCT指導組 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,針對社區(qū)獲得性肺炎（CAP）患者PCT指導臨床抗生素的使用,如何確定何時停用抗生素的困難:*多達 40% 的CAP病人不出現(xiàn)發(fā)熱*>70%推測為細菌感染的CAP 病人鑒定不出致病細菌,結(jié)果表明：使用PCT指導抗生素的使用,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 (標準組), n=151 PCT 指導組PCT 指導下，在病人到達醫(yī)院當天，抗生素使用減少14%， (99% Vs 85%), 在整個療程中，PCT指導組的療程時間為5天，標準組為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ICU患者的抗生素治療,Hochreiter et al., Anaesthesist 2008;57:571-577,標準: 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,抗生素治療時間:

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

25、血清PCT水平是否能在不增加嚴重并發(fā)癥風險的情況下,最大程度地減少濫用抗生素對象：2006年10月-2008年3月瑞士6家醫(yī)院的1359例嚴重LRTI患者設(shè)計：該研究是一項多中心、非劣性、隨機控制研究將入選患者隨機分為對照組和PCT指導治療組(PCT組)對照組根據(jù)標準指南確定的抗生素治療方案，PCT組則同時參考血清PCT水平終點：死亡、入ICU、發(fā)生并發(fā)癥以及30天內(nèi)復發(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組與對照組抗生素使用比較,PCT組抗生素使用時間低于對照組,PCT組的總體抗生素使用水平比對照組平均低25.7%~38.7%,研究后列入時間(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PCT濃度的變化，提示抗生素治療的成功與否,隨著患者對抗生素治療的響應，引起了PCT血中濃度水平的典型變化過程,持

36、續(xù)升高的PCT水平，提示比較差的預后（程度加重，死亡）,連續(xù)的監(jiān)測PCT血中濃度 可以更好的評估患者的預后,嚴重外傷導致膿毒血癥患者，生存者,PCT呈快速下降趨勢，預示著成功的治療效果（感染控制、存活）,連續(xù)的監(jiān)測PCT血中濃度 可以更好的評估患者的預后,臨床應用,如果PCT非常低： 嚴重細菌感染的可能性不大 抗生素應用是有問題的 (<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- 如果病人有高風險（免疫抑制，... ...）,PCTbest performing biomarker for bacterial infection/sepsis,細菌感染后快速升高,細菌感染時高的靈敏度和特異性,感染的嚴重程度,快速反映抗生素的治療效果,,,,,總結(jié),早期診斷,改善細菌感染/膿