杨 毅 邱海波 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 Module 2: HAP - New 医院获得性感染/肺炎 防治进展 杨 毅 邱海波 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

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 早期的有效的经验性治疗 降阶梯策略 MDR耐药的预防

定义 Hospital-acquired pneumonia (HAP) Module 2: HAP - New 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 clinic Slide 3 Based on the national guidelines for initial empiric treatment of patients with hospital-acquired pneumonia (HAP), proposed by the American Thoracic Society (ATS), HAP is defined as pneumonia occurring >48 hours after admission and excluding any infection that is incubating at the time of admission. HAP is a major cause of morbidity and mortality, especially in the complex environment of the intensive care unit (ICU), and is the second most common nosocomial infection in the United States. The lack of sensitive diagnostic methods and the increasing prevalence of nosocomial pathogens with multiple antibiotic resistance complicate patient management. HAP patient deaths directly attributable to infection have been estimated to be as high as 50%, with even higher mortality rates if bacteremia or certain pathogens are involved1 ATS. Am J Respir Crit Care Med 2005;171:388

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 uncommon Am J Respir Crit Care, 2002;165:867 MMWR Recomm Rep, 2004;53(RR-3):1-36

Extra-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 Jimenez et al. Crit Care Med 1989, 17:882-885. Leu et al. Am J Epidemiol 1989, 129:1258-1267 Fagon et al. Am J Med1993, 94:281-288.

VAP对患者医疗费用和预后的影响 高病死率 33-50% attributable mortality MDR infection Module 2: HAP - New VAP对患者医疗费用和预后的影响 高病死率 33-50% attributable mortality MDR infection P<0.001 近期对美国一个数据库的分析显示，与非VAP患者相比，VAP患者机械通气时间、ICU住院时间及总住院时间均显著延长。因此，VAP无疑将增加医疗资源的消耗及医疗费用的支出。另一方面，机械通气及住院时间的延长又可以进一步增加患者发生VAP的风险，使得患者进入到恶性循环中。 J Rello et al Epidemiology & outcomes of VAP in a large US database. (MediQual-Profile database by CIC) Chest 122:2115-21, Dec. 2002

MDR－Multi-Drug-resistance 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 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

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

MRSA/铜绿假单胞菌血症－病死率高 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]

Acinetobacter in critically ill patients: High mortality and LOS in ICU Design: Pairwise matched 1:1 case-control study Crit Care Med, 1999, 27(9): 1794-1799

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) Module 2: HAP - New 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 staff G+ high high G- low low

HAP 发病机理 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 MRSA* Module 2: HAP - New 发病机理 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 Colonization 　　　　　　　　Aspiration HAP MRSA*

MDR危险因素----MV和既往抗生素应用 Module 2: HAP - New MDR危险因素----MV和既往抗生素应用 135 episodes in ICU Variable OR P MV>7d 6.0 .009 Prior ABs 13.5 <.001 Broad ABs 4.1 .025 Am J Respir Crit Care Med. 1998;157:531

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 Antibiotic MDR- Enterobacter n/% P Any antibiotic Yes 36/103 35% No 1/26 4% 0.002 3th cephalosporin 22/32 69% 14/71 20% 0.001 Ann Inter Med, 1991, 115: 585

MDR的危险因素----Quinolone应用 Pseudomonas aeruginosa的耐药率 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

MDR的危险因素----Meropenem应用 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 Arch Intern Med, 2002, 162: 1515

MDR的危险因素----Meropenem应用 Efflux pump AdeDE was identified in acinetobacters belonging to genomic DNA group 3 Amikacin Ceftazidime Chloramphenicol Ciprofloxacin Erythromycin Meropenem Rifampin, Tetracycline. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,. 2004, 48(10). 4054–4055

MDR的危险因素--Antibiotics policies Preferential use Special concerns 3th cephalosporin select: VRE ESBLs Acinetobacter Baumannii, Fungus Fluoroquinolone select MRSA Quino-resi-G- Carbapenem-resi-P aeruginosa Meropenem select: Meropenem-resi MDR P aeruginosa

HAP / VAP / HCAP合并MDR感染 危险因素 Module 2: HAP - New 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 Slide 22 Oropharyngeal or tracheal colonization by pathogenic bacteria, particularly enteric gram-negative bacilli and P. aeruginosa, followed by subclinical microaspiration of secretions is the most common route of bacterial entry into the respiratory tract.4 Microaspiration is common, and the incidence of enteric gram-negative bacilli colonizing the oropharynx of ICU patients increases markedly with the length of hospitalization.4 Prolonged mechanical ventilation is the most important factor associated with HAP, developing in up to 40% of patients requiring more than 48 hours of ventilation.4 The endotracheal tube impairs normal lower respiratory tract immune defenses such as coughing and mucociliary clearance, facilitating infection. Other factors that may influence the progression of HAP include advanced age, history of smoking, chronic obstructive pulmonary disease (COPD), malnutrition, and surgical procedures, particularly thoracic and abdominal interventions.1 Inhalation of pathogens via contaminated equipment, hematogenous spread, and direct inoculation also occur but are less frequent.4 ATS. Am J Respir Care Med 2005;171:388

HAP的临床诊断 临床诊断: New or progressive infiltrate PLUS Module 2: HAP - New 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 Slide 23 A presumptive clinical diagnosis of pneumonia is often made when patients develop a new radiological infiltrate associated with fever, leukocytosis, and purulent tracheal secretion, and when microorganisms are isolated by nonquantitative analysis of endotracheal aspirates.1 This clinical approach may lead to an overestimation of the incidence of HAP because cases of tracheobronchial colonization and non-infectious etiologies mimicking HAP may be included in the diagnosis. Therefore, patients may be exposed to antibiotics unnecessarily, potentially leading to the emergence of resistant pathogens and drug-related toxicity. Furthermore, this approach may delay the diagnosis of the true cause of fever and pulmonary infiltrate.1 Chest, 1997, 112: 445-457 Am J Respir Crit Care Med, 2002, 165: 867-903 Am J Surg, 1996, 171: 570

HAP的实验室诊断 定量培养标准： Antibiotic use more appropriate、accurate Module 2: HAP - New 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 Slide 24 In contrast to clinical diagnosis, invasive diagnostic methods, including quantitative cultures of specimens obtained by a bronchoscopic protected specimen brush or bronchoalveolar lavage, have also been evaluated. A recent randomized study of invasive and non-invasive (clinical) strategies for diagnosing HAP demonstrated that quantitative bronchoscopic specimen cultures (invasive) lead to more appropriate use of antibiotics (i.e., fewer inappropriate treatments and shorter treatment courses), which is followed by improved survival. However, it is important to note that these invasive bronchoscopic procedures are also technically challenging and not universally available to health care institutions.10 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 Module 2: HAP - New 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 washing Ignaz Philipp Semmelweis (1818-1865) NOW Hand washing --- important underused measure to prevent NP 漂白粉消毒手

消毒剂对手部细菌的清除作用 % log 60 180分钟 消毒后时间 99.9 3.0 99.0 2.0 含有乙醇的刷手液 （70%异丙醇） 60 180分钟 消毒后时间 99.9 3.0 99.0 2.0 含有乙醇的刷手液 （70%异丙醇） 杀灭细菌比例 90.0 1.0 抗菌肥皂 （4%洗必太） 普通肥皂 0.0 0.0 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 VAP Must be considered When handling respiratory secretions During patient contact when the patient carries an MDR pathogen (MRSA)

Rello J. Crit Care Med 2003; 31:2544 –2551 Module 2: HAP - New B.气管插管与机械通气 (1)缩短MV时间 根据Washington University at St. Louis的一项研究显示，多数患者可以在接受机械通气3—5天内发生呼吸机相关性肺炎(VAP)，多数患者在10天内发生VAP。 Ibrahim EH et al. Chest 2001，120:555-61 Rello J. Crit Care Med 2003; 31:2544 –2551

气管插管与机械通气 (2)提倡NIV---COPD exacerbation and cardiogenic edema Case–control study in France N=50 pats with COPD exacerbation and cardiogenic pul edema NIV MV P MV时间 6d 10d 0.01 LOS of ICU 9d 15d 0.02 JAMA 2000, 284:2361-2367.

气管插管与机械通气 (3)避免经鼻插管 经鼻/口插管后1周鼻窦炎和VAP患病率 Rouby JJ, et al. Am J Respir Crit Care Med. 150: 776~783

Re-intubation for NP OR=5.94 气管插管与机械通气 (4)避免再插管 Case-match study n=40 Previous duration of MV =2d Am J Respir Crit Care Med 1995, 152:137 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 Hosp stay/d 35.6 31.5 0.4 Re-intubation for NP OR=5.94

气管插管与机械通气 (5)预防鼻窦炎 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 (6)声门下吸引 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 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 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 Design of endotracheal tubes --持续性声门下吸引

气管插管与机械通气 (7)气囊压力 Risk factors for NP/multivariate analysis N=83 Variable RR Failure of CASS 5.29 Low intracuff pressure 2.51 Coma 1.71 Continuous sedation 0.42 Antibiotic use 0.10 Am J　Respir Crit Care Med 1996, 154:111-115.

气管插管与机械通气 (8)呼吸机管路的更换频率 Randomized study n=73 pats who need MV >48h 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% 频繁更换呼吸机管路对预防VAP并无益处

气管插管与机械通气 (9) 湿化与HME HEM reduced hosp-, not community-acquired VAP HEM reduced ICU stay HEM reduced circuit cost Kirton OC. Chest 1997, 112:1055-1059.

C. 误吸/体位与营养 (1)体位与误吸 Aspiration pattern: time dependent for prone position Torres AT. Ann Inter Med, 1992, 116: 540

误吸/体位与营养 (2) 经鼻胃管/鼻空肠管营养 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

Effects of sucralfate/H2-RAs on NP in MV pats D. 溃疡预防/血糖控制 (1)溃疡预防 Effects of sucralfate/H2-RAs on NP in MV pats 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 Clincally important bieeding Nosocomial pneumonia Mortality N Engl J Med 1998; 338: 791-797

Intensive Insulin Therapy in critically ill D. 溃疡预防/血糖控制 (2)血糖控制 Intensive Insulin Therapy in critically ill Number=1548 Conventional Insulin Number 783 765 Death 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) N Engl J Med 2001;345:1359-67

口鼻咽腔/肠道去污染 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:　　

Initial empiric antibiotic therpy: Appropriate and Adequate HAP的抗生素治疗 Appropriate Etiologic organism is sensitive to the therapeutic agent Adequate Correct antibiotic Optimal dose Correct route of administration to ensure penetration at the site of infection Use of combination therapy if necessary Initial empiric antibiotic therpy: Appropriate and Adequate ATS/IDSA. Am J Respir Crit Care Med 2005;171:388-416

Gain in mortality in Patients With Sepsis Module 2: HAP - New 早期有效抗感染治疗的重要性 Gain in mortality in Patients With Sepsis % Mortality Activated C protein Bernard GR et al. N Engl J. Med 2001;344:699-709. 31% 25% 10 20 30 40 50 60 70 -6% Hydrocortisone Annane et al. JAMA 2002;288:862-871 63% 53% -10% Early goal 47% 30% -17% Rivers E et al. NEJM 2001; 345:1368-73 Adequate ATB therapy Valles J et al. Chest 2003;123:1615-1624. 63% 31% -32% The graph above illustrates results from three separate studies showing that treatment, in this case treatment with activated C protein, hydrocortisone, or adequate antibiotic therapy, impacts mortality. A prospective, randomized, double-blind, multicenter, placebo controlled 28-day study was conducted from July 1998 through June 2000 to evaluate the effects of drotrecogin alfa activated (activated protein C) in patients (n=1728) with severe sepsis and a known or suspected infection.7 Patients had to have the following within a 24-hour period: three or more signs of systemic inflammation and the sepsis-induced dysfunction of at least one organ or system, lasting no longer than 24 hours. Drotrecogin alfa activated was administered by infusion at 24 mg/kg body weight per hour, for a total of 96 hours. At 28 days after infusion, 31% (259/840) of the placebo group and 25% (210/850) of the treatment group had died (p=0.005), representing a 19.4% reduction in the relative risk of death and a 6.1% absolute reduction in the risk of death. A randomized, double-blind, parallel group, multicenter, 7-day, placebo controlled study was conducted in France between 9 February 1995 and 15 March 1999 to evaluate whether hydrocortisone (50 mg bolus every 6 hours) and fludrocortisone (one 50 mg tablet daily, administered nasogastrically over 30 seconds) therapy would improve 28-day survival in patients (n=300) with septic shock, including those with adrenal insufficiency. 16 At day 28, 63% of placebo group patients (73 of 115) and 53% of corticosteroid group patients (60 of 114) died (p=0.04; relative risk of death 0.83). The authors concluded that study hydrocortisone therapy significantly reduced 28-day mortality in patients with septic shock, including those with relative adrenal insufficiency. In a prospective, multicenter study conducted in 30 ICUs in Spain from April to December 1993 and April to December 1998, 393 patients were diagnosed with bloodstream infections, defined as true positive blood culture finding on ICU admission within first 48 h of ICU stay.15 In this study, inappropriate antimicrobial treatment was defined as microbiological documentation of blood culture infection that was not effectively treated when the causative pathogen and its antibiotic susceptibility were known. A total of 63% of patients (290/339) who received appropriate treatment survived compared with 31% (49/339) of those who received inappropriate treatment. Without With

Impact of adequate empirical antibiotic therapy on the outcome of pats admitted to ICU with sepsis 死亡： 绝对危险度下降23% CCM, 2003, 31: 2742

HAP经验性抗生素的选择 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 Spectrum Therapy for MDR Pathogens ATS. Am J Respir Crit Care Med. 2005, 171: 388-416

低危MDR感染患者的抗生素选择 Potential Pathogen Recommended Antibiotic Module 2: HAP - New 低危MDR感染患者的抗生素选择 Potential Pathogen Streptococcus 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 Moxifloxacin Ciprofloxacin Ampicillin/sulbactam Ertapenem Slide 47 The core organisms for group 1 include S. pneumoniae, methicillin-sensitive S. aureus (MSSA), H. influenzae, and enteric gram-negative bacilli. The ATS recommends monotherapy for HAP patients in this group, including second-generation cephalosporins, a -lactam/-lactamase inhibitor combination (piperacillin/tazobactam, ticarcillin/clavulanate), or a non-pseudomonal third-generation cephalosporin (cefotaxime or ceftriaxone). A fluoroquinolone, or clindamycin plus aztreonam, may be considered for penicillin-allergic patients, provided that S. pneumoniae is ruled out. ATS. Am J Respir Crit Care Med. 2005, 171: 388-416

高危MDR感染患者的抗生素选择 Potential Pathogens Therapy P. aeruginosa Module 2: HAP - New 高危MDR感染患者的抗生素选择 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 Slide 48 The most challenging issue in treating HAP is selecting appropriate empiric antibiotics for patients in group 3. ATS recommends the addition of antimicrobial agents effective against P. aeruginosa and Acinetobacter species to the group 1 antibiotics; this includes an aminoglycoside or fluoroquinolone in combination with an antipseudomonal b-lactam, with or without a b-lactamase inhibitor (e.g., piperacillin/tazobactam), antipseudomonal cephalosporin, aztreonam, or carbapenem. Vancomycin is recommended for patients at risk of S. aureus infection until MRSA is excluded (in groups 2 and 3). ATS. Am J Respir Crit Care Med. 2005, 171: 388-416

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 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） 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） 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 SICU 115 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 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 months CCM 2003, 31(7): 1908-14

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% ICU mortality of VAP 40.6% 37.2% NS Am J Respir Crit Care Med 2000, 162: 837

减少抗生素疗程－预防MDR 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) JAMA, 2003, 290: 2598

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 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

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