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医院获得性感染 / 肺炎 防治进展

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 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. Hospital-acquired pneumonia (HAP) 入院48 h 后 Ventilator-associated pneumonia (VAP) 插管 48– 72h

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医院获得性感染 / 肺炎 防治进展

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  1. 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

  2. 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

  3. 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 clinic ATS. Am J Respir Crit Care Med2005;171:388

  4. 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 • 6to 20fold 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

  5. 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.

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

  7. MDR－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

  8. 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

  9. rGNR:入住ICUMVCRRT抗生素更换住院时间病死率

  10. 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

  11. 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]

  12. 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

  13. 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？？？

  14. 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

  15. ColonizationAspiration MRSA* 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

  16. 135 episodes in ICU MDR危险因素----MV和既往抗生素应用 Am J Respir Crit Care Med. 1998;157:531

  17. 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

  18. Amikacin Ceftazidime Ciprofloxacin Imipenem Piperacillin Piperacillin/ tazobactam MDR的危险因素----Quinolone应用 Pseudomonas aeruginosa的耐药率 * Neuhauser MM et al. JAMA 2003;289:885-888 *Itokazu GS et al. Clin Infect Dis 1996;23:779-784

  19. 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

  20. 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

  21. 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

  22. 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

  23. 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: 445-457 Am J Respir Crit Care Med, 2002, 165: 867-903 Am J Surg, 1996, 171: 570

  24. 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

  25. 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

  26. 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

  27. 消毒剂对手部细菌的清除作用 消毒后时间 0 180分钟 60 % log 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.

  28. 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)

  29. B.气管插管与机械通气(1)缩短MV时间 Ibrahim EH et al. Chest 2001，120:555-61 Rello J. Crit Care Med 2003; 31:2544 –2551

  30. 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 JAMA 2000, 284:2361-2367.

  31. 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

  32. 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 for NP OR=5.94

  33. 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

  34. Hi-Lo Vac Endotracheal Tube 套囊充气管 套囊上吸引管 “常规” 吸痰口 声门下间隙 套囊上吸引口 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 • 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

  35. 气管插管与机械通气(7)气囊压力 Risk factors for NP/multivariate analysis N=83 Am JRespir Crit Care Med 1996, 154:111-115.

  36. 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 • 频繁更换呼吸机管路对预防VAP并无益处

  37. 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.

  38. 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

  39. 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

  40. 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

  41. D. 溃疡预防/血糖控制(2)血糖控制 Intensive Insulin Therapy in critically ill N Engl J Med 2001;345:1359-67

  42. 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:

  43. -10% -32% -6% -17% 70 63% 60 63% 63% 53% 53% 50 47% 40 % Mortality 30 31% 31% 31% 30% 25% 25% 20 10 0 Activated C protein Bernard GR et al. N Engl J. Med 2001;344:699-709. Hydrocortisone Annane et al. JAMA 2002;288:862-871 Adequate ATB therapy Valles J et al. Chest 2003;123:1615-1624. Early goal Rivers E et al. NEJM 2001; 345:1368-73 早期有效抗感染治疗的重要性 Gain in mortality in Patients With Sepsis With Without

  44. 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

  45. Empiric Antibiotic Therapy for HAP HAP,VAP, or HCAP suspected (all disease severity) Late onset (>5 days) or risk factors forMDR Pathogens Yes No Limited Spectrum Therapy Broad Spectrum Therapy for MDR Pathogens HAP经验性抗生素的选择 ATS. Am J Respir Crit Care Med. 2005, 171: 388-416

  46. 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 or Moxifloxacin or Ciprofloxacin or Ampicillin/sulbactam or Ertapenem 低危MDR感染患者的抗生素选择 ATS. Am J Respir Crit Care Med. 2005, 171: 388-416

  47. Potential Pathogens P. aeruginosa ESBL (+) K. pneumoniae Acinetobacter species MRSA L. pneumophila Therapy Antipseudomonal cephalosporin (cefepime, ceftazidime) or Antipseudomonal carbapenem (İmipenem, meropenem) or Piperacillin-tazobactamplus Ciprofloxacin or levofloxacin or Aminoglycoside Linezolid or vancomycin 高危MDR感染患者的抗生素选择 ATS. Am J Respir Crit Care Med. 2005, 171: 388-416

  48. 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 *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

  49. 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

  50. 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

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