医院获得性感染 / 肺炎防治进展

杨 毅 邱海波杨 毅 邱海波东南大学医学院附属中大医院东南大学医学院附属中大医院

东南大学急诊与危重病医学研究所东南大学急诊与危重病医学研究所

内容提要内容提要• HAP 流行病学和 MDR 在 ICU 的重要性• HAP 的机制与 MDR 的危险因素• HAP 的诊断• HAP 的非抗生素预防策略• HAP 的抗生素治疗策略

– 早期的有效的经验性治疗– 降阶梯策略– MDR 耐药的预防

定义定义•Hospital-acquired pneumonia (HAP)

– 入院 48h 后•Ventilator-associated pneumonia (VAP)

– 插管 48–72h

•Healthcare-associated pneumonia (HCAP)– Any patient

–出现感染的 90 天内在 ICU 住院 2 天以上–Resided in a nursing home –Received recent iv antibiotic, chemotherapy or wound care last 30 days

–Attended a hospital or hemodialysis clinicATS. Am J Respir Crit Care Med 2005;171:388

流行病学流行病学•高发病率 --- 最常见的院内感染之一 ( 第二位 )

– 5-15 cases / 1000 admissions

– 6 to 20 fold higher in MV patients

– 25% of all ICU infections

– >50% of all antibiotics prescribed

• 常见病原菌 - Aerobic gram-negative bacilli

P. aeruginosa 、 K. pneumoniae 、 Acinetobacter spp.

- Gram-positive ： MRSA - Anaerobes are uncommonAm J Respir Crit Care, 2002;165:867

MMWR Recomm Rep, 2004;53(RR-3):1-36

Extra-ICU/hosp stayExtra-ICU/hosp stay

• NP/VAP: ICU stay increased 3 fold

• 10 ~32 d additional hosp stay

• 9.2 d of additional hospital stay

• Median length of ICU stay for VAP 21 d vs 15 d for control pat

Fagon et al. Am J Med1993, 94:281-288.

Jimenez et al. Crit Care Med 1989, 17:882-885.

Leu et al. Am J Epidemiol 1989, 129:1258-1267

VAP 对患者医疗费用和预后的影响VAP 对患者医疗费用和预后的影响

P<0.001

J Rello et al Epidemiology & outcomes of VAP in a large US database.(MediQual-Profile database by CIC) Chest 122:2115-21, Dec. 2002

•高病死率 –33-50% attributable mortality

–MDR infection

MDR － Multi-Drug-resistanceMDR － Multi-Drug-resistance

• G- 菌对四类抗生素中 3/4 类耐药– Ceftazidine, Ciprofloxacin, Gentamicin,

Imipenem

– Pseudomonas aeruginosa Acinetobacter species

– ESBLs/AmpC

• COS, CCOS PDR

• G+– MRSA

G- 杆菌耐药对预后的影响G- 杆菌耐药对预后的影响• Prospective cohort study.

– Dec 1996 to Sep 2000 – Inpatient surgical wards at a university hosp– N=924 pats with GNR infections

• Outcomes were compared between GNR infections with and without antibiotic res

• rGNRs: resistant to one or more of the following– all aminoglycosides, including amikacin– all cephalosporins– all carbapenems– all fluoroquinolones

Crit Care Med 2003; 31:1035–1041

rGNR:

入住 ICU

MV

CRRT

抗生素更换

住院时间

病死率

rGNR:

入住 ICU

MV

CRRT

抗生素更换

住院时间

病死率

治疗过程中铜绿假单胞产生耐药---- 病死率明显增加

治疗过程中铜绿假单胞产生耐药---- 病死率明显增加

• N=489 pats with NP– 耐药：对 PIP, CFZ, IMP, CIP 至少 1 个耐药– 入组时耐药 n=144– 治疗过程中 (14d) 出现耐药 n=30

• Mortality:– 敏感组 7.5% vs 耐药组 7.6% (p=0.96, RR0.94)

– 治疗过程持续敏感组 6.3% vs 新耐药组 26.6% (p=0.03, RR 2.9)

• 继发性菌血症– 治疗过程持续敏感组 1.4% vs 新耐药组 14% (p<0.001, RR 9)

Arch Intern Med, 1999, 159: 1127

• Hospital mortality: 17.2%

• P aeruginosa vs MSSA [30.6% vs 16.2%, p 0.036]

• P aeruginosa and MRSA [30.6% vs 13.5%, p 0.007]

MRSA/ 铜绿假单胞菌血症－病死率高MRSA/ 铜绿假单胞菌血症－病死率高

Acinetobacter in critically ill patients:High mortality and LOS in ICU

Acinetobacter in critically ill patients:High mortality and LOS in ICU

Crit Care Med, 1999, 27(9): 1794-1799

Design: Pairwise matched 1:1 case-control study

发病机理

病原体来源：患者呼吸道和消化道的定植菌医疗设备的致病菌 ( 呼吸机／导管 )环境的致病菌 ( 空气／水／飞沫等 )其他病人和工作人员携带致病菌的传播传播途径： 误吸经空气血源性感染？？？

Air of word

G+ G-ICU 26% 8.1%Other word 23.6% 2.6% P >0.05 >0.04环境和手－－主要为 G+ 菌

Hand of Pat Hand of staffG+ high highG- low low

Colonization 　　　　　　　　Aspiration

HAP

MRSA*

传播途径： 误吸－最重要的 NP/VAP 的原因经空气和血源性感染－并不常见

发病机理

MDR 危险因素 ----MV 和既往抗生素应用

135 episodes in ICU

0

5

10

15

20

25

%

+/+ –/+ +/– –/–

P. aeruginosa A. baumannii MRSA

Am J Respir Crit Care Med. 1998;157:531

Variable OR P

MV>7d 6.0 .009

Prior ABs 13.5 <.001

Broad ABs 4.1 .025

MDR 的危险因素 --- 抗生素应用 (3G Cepha)

MDR 的危险因素 --- 抗生素应用 (3G Cepha)

• Prospective study n=129

• Antibiotic therapy for Enterobacter bactermia

• 首次血培养 MDR- Enterobacter 与 2w 前抗生素关系

Ann Inter Med, 1991, 115: 585

Antibiotic MDR- Enterobacter n/% P

Any antibiotic

Yes 36/103 35%

No 1/26 4% 0.002

3th cephalosporin

Yes 22/32 69%

No 14/71 20% 0.001

0%

5%

10%

15%

20%

25%

30%

1990-1993

1994 1995 1996 1997 1998

Years

% R

esis

tanc

eMDR 的危险因素 ----Quinolone 应用

Amikacin

Ciprofloxacin

Imipenem

Piperacillin

Piperacillin/ tazobactam

Ceftazidime

Neuhauser MM et al. JAMA 2003;289:885-888

*Itokazu GS et al. Clin Infect Dis 1996;23:779-784

*

Pseudomonas aeruginosa 的耐药率

• Antibiotics: – Aminoglycosides

– Fluoroquinolones

– beta-lactamase inhibitor combinations

– Carbapenems

– all cephalosporins + aztreonam

• Multivariate analysis for the rate of carbapenem-res A baumannii and CFZ-res A baumannii– Only cephalosporins + aztreonam

– P=0.04 P=0.03

MDR 的危险因素 ----Meropenem 应用

Arch Intern Med, 2002, 162: 1515

• Efflux pump AdeDE was identified in acinetobacters belonging to genomic DNA group 3– Amikacin– Ceftazidime– Chloramphenicol– Ciprofloxacin– Erythromycin– Meropenem– Rifampin,– Tetracycline.

MDR 的危险因素 ----Meropenem 应用

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,. 2004, 48(10). 4054–4055

Preferential use

Special concerns

MDR 的危险因素 --Antibiotics policiesMDR 的危险因素 --Antibiotics policies

3th cephalosporin select: -VRE ESBLs Acinetobacter Baumannii, Fungus

Meropenem select: -Meropenem-resi MDR P aeruginosa

Fluoroquinolone select-MRSA Quino-resi-G- Carbapenem-resi-P aeruginosa

HAP / VAP / HCAP 合并 MDR 感染

危险因素

HAP / VAP / HCAP 合并 MDR 感染

危险因素 • Antimicrobial therapy in preceding 90 days

• Current hospitalization of 5 days or more

• High frequency of antibiotic resistance in

the community or in the spesific hospital

• Presence of risk factors for HCAP

• Immunosuppressive disease and/or therapy

ATS. Am J Respir Care Med 2005;171:388

HAP 的临床诊断HAP 的临床诊断临床诊断 :• New or progressive infiltrate PLUS new onset fever, leukocytosis, or purulent sputum, and organisms isolated by non- quantitative analysis of endotracheal

aspirate example: Gram stain• Drawback – relatively nonspecific• CPIS-low sensitivity and specificity• Need bacteriologic strategy

Chest, 1997, 112: 445-457Am J Respir Crit Care Med, 2002,

165: 867-903Am J Surg, 1996, 171: 570

HAP 的实验室诊断HAP 的实验室诊断

•定量培养标准：– bronchoscopic PSB (>103 CFU/ml)

– bronchoalveolar lavage (>104 CFU/ml)

– endotracheal aspirate (>106 CFU/ml)

•Antibiotic use more appropriate 、 accurate

•Improved survival Baughman RP. Chest. 2000;117:203S

Fagon JY,et al. Ann Intern Med 2000;132:621

Cook D, et al. Chest. 2000;117:195S

非抗生素治疗策略 气管插管与机械通气

插管路径 NIV/IV 气囊的管理 声门下的积液 湿化与雾化 管路与冷凝水 MV 时间

误吸 / 体位 体位 / 胃肠道返流 营养途径

口鼻咽腔 / 肠道定植 溃疡预防 / 血糖控制 ICU 的医疗强度

A. 一般预防措施 ---Hand washingA. 一般预防措施 ---Hand washing

漂白粉消毒手

Ignaz Philipp Semmelweis(1818-1865)

Hand washing ---important underused measure to prevent NP

NOW

消毒剂对手部细菌的清除作用消毒剂对手部细菌的清除作用

99.9 3.0

99.0 2.0

90.0 1.0

0.0 0.0

含有乙醇的刷手液（ 70% 异丙醇）

抗菌肥皂（ 4% 洗必太）

普通肥皂

杀灭

细菌

比例

% log 0 180 分钟60 消毒后时间

Hosp Epidemiol Infect Control, 2nd Edition, 1999.

The use of protective gowns and gloves during patient contact can not be recommended

for the routine prevention of VAPMust be considered

When handling respiratory secretions

During patient contact when the patient carries an MDR pathogen (MRSA)

B. 气管插管与机械通气(1) 缩短 MV 时间

B. 气管插管与机械通气(1) 缩短 MV 时间

Rello J. Crit Care Med 2003; 31:2544 –2551Ibrahim EH et al. Chest 2001 ， 120:555-61

• Case–control study in France

• N=50 pats with COPD exacerbation and cardiogenic pul edema

0%

10%

20%

30%

40%

50%

60%

Nosocomi al i nf(P<0. 001) NP(P=0. 04) Anti bi oti c for NI (0. 01) Crude mortal i ty(p=0. 002)

NIVMV

JAMA 2000, 284:2361-2367.

气管插管与机械通气(2) 提倡 NIV---COPD exacerbation and cardiogenic

edema

气管插管与机械通气(2) 提倡 NIV---COPD exacerbation and cardiogenic

edema

NIV MV P

MV 时间

6d 10d 0.01

LOS of ICU

9d 15d 0.02

95.50%

22.50%

0%

20%

40%

60%

80%

100%

/%鼻

窦炎

患病

率

经鼻插管 经口插管

Rouby JJ, et al. Am J Respir Crit Care Med. 150: 776~783

经鼻 / 口插管后 1 周鼻窦炎和 VAP 患病率

67.00%

43.00%

0%

20%

40%

60%

80%

VAP

/%发

生率

鼻窦炎者 非鼻窦炎者

气管插管与机械通气(3) 避免经鼻插管

气管插管与机械通气(3) 避免经鼻插管

Am J Respir Crit Care Med 1995, 152:137

Case-match study n=40Previous duration of MV =2d

气管插管与机械通气(4) 避免再插管

气管插管与机械通气(4) 避免再插管

Re-intubation Controls P

NP/% 47% 10% <0.001

Mortality

Total 35% 20% 0.14

Related 17.5% 0% 0.01

ICU stay/d 19+/-10 14+/12 <0.001

Hosp stay/d 35.6 31.5 0.4

Re-intubation for NP OR=5.94

•患者魏XX，男，35岁•胆囊切除术，心肺脑复苏术后入院

•鼻饲胃管14天•不明原因发热, 40oC

•副鼻窦CT检查May-8

气管插管与机械通气(5) 预防鼻窦炎

气管插管与机械通气(5) 预防鼻窦炎

普通气管插管 /气管切开管

• 分泌物在声门下间隙潴留

• 声门下气道及口鼻咽腔细菌定植

• 声门下分泌物及口鼻咽腔分泌物的误吸

Hi-Lo Vac Endotracheal Tube

套囊上吸引管套囊充气管

套囊上吸引口

“ 常规” 吸痰口

声门下间隙

Design of endotracheal tubes -- 持续性声门下吸引

气管插管与机械通气(6) 声门下吸引

气管插管与机械通气(6) 声门下吸引

Am J Respir Crit Care Med 1996, 154:111-115.

Risk factors for NP/multivariate analysisN=83

气管插管与机械通气(7) 气囊压力

气管插管与机械通气(7) 气囊压力

Variable RR

Failure of CASS 5.29

Low intracuff pressure

2.51

Coma 1.71

Continuous sedation

0.42

Antibiotic use 0.10

33%39%

8%

42%

0%

10%

20%

30%

40%

50%

NP /%

Antibiotic group(P>0.02)

Non-antibioticgroup (P<0.01)

>20

<20

Randomized study n=73 pats who need MV >48h

气管插管与机械通气(8) 呼吸机管路的更换频率

气管插管与机械通气(8) 呼吸机管路的更换频率

Ventilator circuit change

q48h No P

VAP 31.4% 28.6% 0.8

Duration of MV 10.1d 9.1d 0.7

Mortality 17.1% 25% 0.4

Deaths with VAP 8.6% 7.1% 0.8

•频繁更换呼吸机管路对预防 VAP 并无益处

6%

16%

0%

5%

10%

15%

20%

HME (n=140) Humidifier (n=140)

VAP/

%

2443

3892

0

1000

2000

3000

4000

HME (n=140) Humidifier (n=140)

Cir

cuit

cost

/gro

up

HEM reduced hosp-, not community-acquired VAPHEM reduced ICU stayHEM reduced circuit cost

Kirton OC. Chest 1997, 112:1055-1059.

气管插管与机械通气(9) 湿化与 HME

气管插管与机械通气(9) 湿化与 HME

• Aspiration pattern: time dependent for prone position

Torres AT. Ann Inter Med, 1992, 116: 540

C. 误吸 / 体位与营养(1) 体位与误吸

C. 误吸 / 体位与营养(1) 体位与误吸

• Multicenter, prospective, randomized, single-blind study

• Enteral nutrition started in 101 pats during first 36h

• Nasogastric tube vs nasogastrojejunal tube

• Results:– Gastrointestinal complications: 57% vs 25%

P<0.04

– Length of hospital stay and Mortality: no diff

– Incidence of pneumonia: 40% vs 32% (no diff)

Montejo JC. CCM, 2002, 30: 796-800

误吸 / 体位与营养(2) 经鼻胃管 / 鼻空肠管营养

误吸 / 体位与营养(2) 经鼻胃管 / 鼻空肠管营养

Effects of sucralfate/H2-RAs on NP in MV patsEffects of sucralfate/H2-RAs on NP in MV pats

2%

19%

24%

4%

16%

23%

0%

10%

20%

30%

1 2 3

rani ti di nesucral fate

Clincally important bieeding

Nosocomial pneumonia

Mortality

N Engl J Med 1998; 338: 791-797

A multicenter, randomized,blinded, placebo-controlled trial

16 ICUs, 1200 patients, MV>48h

Sucralfate 1g/6h in 604 patients

IV ranitidine 50mg/8h in 596 patients

P<0.02

D. 溃疡预防 / 血糖控制(1) 溃疡预防

D. 溃疡预防 / 血糖控制(1) 溃疡预防

Intensive Insulin Therapy in critically illIntensive Insulin Therapy in critically ill

N Engl J Med 2001;345:1359-67

Number=1548 Conventional

Insulin

Number 783 765Death 63(8%) 35(4.6%)Creatinine>221umol/L

96(12.3%) 69(9%)

BUN>19.2mmol/L 88(11.2%) 59(7.7%)RRT 64(8.2%) 37(4.8%)ICU>5d 20.2% 10.6%

Bloodstream infection (n)

61 32 (P<0.003)

Antibiotics for >10 ds (n)

134 86(P<0.001)

D. 溃疡预防 / 血糖控制(2) 血糖控制

D. 溃疡预防 / 血糖控制(2) 血糖控制

• SDD ：可预防 MDR 致病菌爆发流行引起的 VAP ，但不推荐常规应用

• SOD: 　　

口鼻咽腔 / 肠道去污染口鼻咽腔 / 肠道去污染

Gain in mortality in Patients With SepsisGain in mortality in Patients With Sepsis

Without

% M

ort

alit

y

Activated C protein

Bernard GR et al. N Engl J. Med 2001;344:699-709.

31%25%

0

10

20

30

40

50

60

70

31%31%25%25%

-6%

HydrocortisoneAnnane et al. JAMA 2002;288:862-871

63%

53%

63%63%

53%53%

-10%

Adequate ATB therapy

Valles J et al. Chest 2003;123:1615-1624.

63%63%

31%31%

-32%

With

Early goal

47%47%

30%30%

-17%

Rivers E et al. NEJM 2001; 345:1368-73

早期有效抗感染治疗的重要性

Impact of adequate empirical antibiotic therapy on the outcome of pats admitted

to ICU with sepsis

Impact of adequate empirical antibiotic therapy on the outcome of pats admitted

to ICU with sepsis

9%

38%

63%

29%

61%

81%

0%

20%

40%

60%

80%

100%

sepsi s sspesi s sshock

Mort

alit

y /%

AEATIEAT

CCM, 2003, 31: 2742CCM, 2003, 31: 2742

死亡： 绝对危险度下降 23%

Empiric Antibiotic Therapy for HAP

HAP,VAP, or HCAP suspected(all disease severity)

Late onset (>5 days) or risk factors for MDR

Pathogens

No Yes

Limited Spectrum Therapy

Broad SpectrumTherapy for MDR Pathogens

ATS. Am J Respir Crit Care Med. 2005, 171: 388-416

HAP 经验性抗生素的选择

低危 MDR 感染患者的抗生素选择低危 MDR 感染患者的抗生素选择

Potential PathogenStreptococcus pneumoniae

Haemophilus influenzae

Methicillin-sensitive Staphylococcus aureus

Enteric gram-negative bacilli

(Antibiotic sensitive) Enterobacter species

Escherichia coli

Klebsiella species

Proteus species

Serratia marcescens

Recommended Antibiotic

Ceftriaxone or Levofloxacin or Moxifloxacin or Ciprofloxacin or Ampicillin/sulbactam or Ertapenem

ATS. Am J Respir Crit Care Med. 2005, 171: 388-416

Potential Pathogens

P. aeruginosa

ESBL (+) K. pneumoniae

Acinetobacter species

MRSA

L. pneumophila

Therapy

Antipseudomonal cephalosporin

(cefepime, ceftazidime) or

Antipseudomonal carbapenem

(İmipenem, meropenem) or

Piperacillin-tazobactam plus

Ciprofloxacin or levofloxacin or

Aminoglycoside

Linezolid or

vancomycin

ATS. Am J Respir Crit Care Med. 2005, 171: 388-416

高危 MDR 感染患者的抗生素选择高危 MDR 感染患者的抗生素选择

起始经验治疗晚发型或具有 MDR 病原菌危险因素的 HAP 、 VAP 和 HCAP 患者和所有重症感染患

者

起始经验治疗晚发型或具有 MDR 病原菌危险因素的 HAP 、 VAP 和 HCAP 患者和所有重症感染患

者

MDR 病原菌 抗生素 * 联合治疗铜绿假单胞菌

肺炎克雷伯菌（ ESBL+ ）

不动杆菌属

抗假单胞菌头孢菌素（头孢他啶、头孢吡肟）或抗假单胞菌碳青霉烯类（亚胺培南、美罗培南）或β- 内酰胺 /β- 内酰胺酶抑制剂（哌拉西林 - 他唑巴坦）加抗假单胞菌氟喹诺酮类（环丙沙星或左氧氟沙星）或氨基糖苷类（阿米卡星、庆大霉素或妥布霉素）

* 抗菌活性范围、抗生素的有效剂量、药动学特性、各种抗菌药物的 不良反应和单药治疗的作用都经过委员会的仔细审核

评价de-escalation 在VAP 抗生素治疗中的意义前瞻性观察性研究 (43m)MICU and SICU115 pats with VAP

121 次 VAP抗生素改变 56.2%, deescalation 抗生素改变的主要原因 ,占 31.4% ICU- mortality 32.2%不合适起始抗生素 9%, 增加 14.4% 病死率

Crit Care Med 2004; 32:2183–2190

抗生素轮换Strategy of antibiotic rotation

抗生素轮换Strategy of antibiotic rotation

• Pellegrin University Hospital, France

• Medical ICU: 16 beds

• Time: 7 years study

• 2856 pats with MV---VAP (early/late onset)

• Period:– 1: 1995-1996 对照– 2: 1997-1998 阶段轮换阶段– 3: 1999-2001 扩大样本轮换

• Rotation: 1 monthsCCM 2003, 31(7): 1908-14

Cycling in the Management of Resistance

Cycling in the Management of Resistance

Cycling protocols (cefepime, pip/tazobactam, IMP, ticarcillin-clavulanic, 可合用Amk/Tob/Net, 限制Cipro等) at 1 month intervals in a MICU

Outcome: resistance in G- and incidence of VAP

Before period (1995-1996): n=1044/After period (1997-998): n=1022 patients with MV > 48h

MDR-铜绿 /洋葱 /不动 /嗜麦牙 : 140 to 79

P. aeruginosa/B. cepacia敏感性 :明显增加

S. aureus: MSSA 40% to 60%

Before- period After-period P

MDR-G- bacteria 42.2% 34.5% 0.06

Clinical suspicion of VAP 28% 19.8% <0.01

Microbiologically documented VAP

22.1% 15.7% <0.01

ICU mortality of VAP 40.6% 37.2% NS

Am J Respir Crit Care Med 2000, 162: 837

• Prospective multi-center randomized study

• Pats with microbiologically proven VAP

• Receive appropriate initial empiric treatment for 8 (n=197) vs 15 d (n=204)

• Mortality and recurrent infection: No diff

• Antibiotic-free days: 13.1d vs 8.7d (P<0.001)

• MDR pathogens emerged significantly less frequently in 8d group than 15d group (42.1% vs 62.4%, P=0.04)

减少抗生素疗程－预防 MDR

JAMA, 2003, 290: 2598JAMA, 2003, 290: 2598

小 结小 结• HAP 发病率高，病死率高• MDR 的流行，进一步增加 HAP 的病死率• 内源性感染的 HAP 的主要机制• 非抗生素预防策略是降低HAP 的关键性措施• 早期有效的抗生素明显降低 HAP 病死率• 降阶梯／抗生素轮替／限制某些抗生素及疗程，

有助于降低MDR

Thank you !!!Thank you !!!