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多重抗藥性菌之處理原則與院內感染防護

多重抗藥性菌之處理原則與院內感染防護. 台大醫院 內科部 主治醫師 盛望徽. 盤尼西林的發現 - 1928. Alexander Fleming 1898-1968. Penicillium notatum. 人類和細菌是一場永不停止的戰爭. The organism will find its way ! (to survive) 道高一尺 , 魔高一丈!. Intracellular organism. Spore formation. Post-Antibiotic Era 後抗生素時代. 伺機性感染及多重抗藥細菌出現 !

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多重抗藥性菌之處理原則與院內感染防護

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  1. 多重抗藥性菌之處理原則與院內感染防護 台大醫院 內科部 主治醫師 盛望徽

  2. 盤尼西林的發現 - 1928 Alexander Fleming 1898-1968 Penicillium notatum

  3. 人類和細菌是一場永不停止的戰爭 The organism will find its way ! (to survive) 道高一尺, 魔高一丈! Intracellular organism Spore formation

  4. Post-Antibiotic Era 後抗生素時代 伺機性感染及多重抗藥細菌出現! • More invasive therapy (侵襲性治療) • More immunocompromised hosts (免疫缺損) • More antimicrobials and selective pressure (抗生素篩選抗藥性病菌) • Spreading to community (MRSA, VRSA, ESBL) Search new antibiotics Control and prevention (environment)

  5. New Antibiotics 2004-2008 • Quinupristin/dalfopristin (Gram+ bacteria, not E. faecalis) • Linezolid (Gram+ bacteria) • Daptomycin (Gram+ bacteria) • Oritavancin, Dalbavancin (Gram+ bacteria, not van A VRE) • Ceftobiprole (anti-MRSA cephalosporin + Pseudomonas) • Tigecycline (Atypicals + anti-MRSA + Acinetobacter, not Pseudomonas) • Teithromycin (S. pneumoniae and atypicals) • Moxifloxacin, Gatifloxacin, Gemifloxacin (GPC, GNB, Anerobes and atypicals, not Pseudomonas) • Doripenem (anti-MRSA Carbapenem) Livermore DM. Clin Microbiol Infect 2004;10S4:1-9.

  6. 新一代的抗生素研發趨緩

  7. Pathogens Causing Nosocomial Infections, NTUH, 1981- 2000 MRSA VRE PRSP MRSA Pseudomonas Acinetobacter Stenotrophomonas ESBL-E. coli, KP Amp-Enterobacter Pseudomonas

  8. Worldwide Epidemiology of Resistant-GNB (SMART)Study for Monitoring Antimicrobial Resistance Trends Paterson, et al. J Antimicrob Chemother 2005

  9. Jan-Dec 2006

  10. Fluoroquinolone-Resistance among Gram-negative Bacilli in Taiwan Example of ciprofloxacin sensitivity • E. coli • K. pneumoniae • Proteus mirabilis • Morganella morganii • Serratia marcescens • Enterobacter cloacae • Pseudomonas aeruginosa 50% FQ-resistant bacterial infection without previous exposure to FQs ! 1985  1997 100%  81% 100%  93% 100%  96% 100%  81% 99%  80% 100%  83% 97%  87% Sheng WH, et al. Diagn Microb Infect Dis 2002

  11. 400 25 PDRAB 328 330 A. baumannii 20.1 20 21.6 % of PDRAB 21.2 281 280 300 254 15 200 159 155 10 135 8.9 8.2 106 103 102 7.1 100 79 78 75 71 70 5 51 23 25 11 0.7 0 0 0 0 0 0 0 0 0 91 93 95 97 99 2001 2003 Pan Drugs Resistant Acinetobacter baumannii (PDRAB)Causing Nosocomial InfectionsNTUH, 1991-2004 % No. of strains

  12. 全抗藥性AB菌(PDRAB)之增加 與抗生素之增加使用有關 Gram/patient-dayx1,000 % of isolates 2003 CRAB, 24.2% CRPA, 16.1% Hsueh PR et al. Emerg Infect Dis 2002;8:132-7.

  13. 細菌發生抗藥性的步驟 抗藥性基因之發生 (基因本身自然突變:自其他生物獲得) 環境選擇性壓力(Selection pressure) (antibiotics use in human and animal) 抗藥性細菌之散佈 (Spread in the environment) (未做好院內感控)

  14. Horizontal Spreads of Antibiotic Resistance Genes • Resistance gene cassettes • Integrons and replicons • Plasmid and conjugated transposon

  15. Acinetobacter baumannii • 葡萄糖非發酵性格蘭氏陰性桿菌，天生具多重抗藥性 • 廣泛存於自然界中(泥土與水)，乾燥環境可存活數週，皮膚、呼吸道及腸胃道為此菌的潛藏處 • 易移生於器械表面，造成院內群突發，加護中心病患、長期住院與低抵抗力病患為易感宿主 • 手套、蒸餾水、靜脈輸液、監視器、床墊、工作人員的手、呼吸器及潮濕瓶與群突發有關 • 危險因子:大手術後、燒傷、使用侵入性設備、重症病患、使用類固醇、慢性肺病、酒癮、癌症及住院時間較長的病患、先前使用過廣效性抗生素

  16. Outbreak of PDRAB at SICU, 2001 • PDRAB colonized over hands of HCW, respirators, chart records, telephone, and air conditioner • Cohort care  vigorous infection control  close ICU ward Sheng WH, et al. Healthcare-associated outbreak due to pan-drug resistant Acinetobacter baumannii in a surgical intensive care unit. J Hosp Infect 2003;53:97-102.

  17. 影響細菌抗藥性發生的因素(主要為醫源環境及抗生素濫用) 宿主 (host) • Increased severity of illness • More severe immunocompromise • Newer devices and procedure 環境 (environment) • Resistance in the community • Infection control and compliance (wash hands…) • Inappropriate use of prophylaxis, empiric antibiotics 病原菌 (pathogen)

  18. 抗藥性細菌的治療策略 如何避免抗藥性細菌發生及傳播 • 治療本身疾病(免疫提升) • 減少不必要之侵襲性治療 • 合理的使用抗生素 • 積極之院內感控

  19. True Pathogen? Colonization? 1. AM: Ampicillin R AMC: Amoxi./Clavu R CZ: Cefazolin R CMZ: Cefmetazole R CTX: Cefotaxime R GM: Gentamicin 10μg R AN: Amikacin S IPM: Imipenem S CIP: Ciprofloxacin R FEP: Cefepime R AZM: Aztreonam R

  20. 先確定病原是否有意義 血液或無菌體液培養(腦脊髓液，肋膜積水..). 痰液培養： • 聽診有囉音或敲診有濁音 • 新發生的膿痰或是痰液的顏色改變。 • 血液培養陽性或由bronchial washing或biopsy培養出菌。 • 肺部X光有新增或惡化的浸潤，開洞或肋膜積水。 泌尿道培養： • 泌尿道症狀及尿液培養有大於105菌落/ml。 • 培養出的微生物需小於三種。 • 泌尿道症狀加上WBC esterase或nitrate陽性，或膿尿(>10 WBC/HPF)或重複培養出同一之細菌>102菌落/ml。 傷口培養： • 必須要有膿液或紅腫熱痛存在，不可只是單純的根據傷口培養結果用藥。 Am J Infect Control 1988;16:128-40.

  21. 合理之抗生素使用為減少敗血症死亡率最主要之因素合理之抗生素使用為減少敗血症死亡率最主要之因素 63% 63% 53% % Mortality 31% 31% 25% Activated C protein Hydrocortisone Adequate Antibiotic therapy YesNo

  22. 經驗性療法 (Empirical therapy) 及早使用抗生素 • 敗血症或敗血性休克的病人。 • 疑似細菌性腦膜炎、急性心內膜炎的病人。 • 白血球缺乏而有發燒的病人。 • 有明顯部位感染情形。 • 病人為老年人、幼童或有免疫機能缺損者 • 院內感染。

  23. 肺炎抗微生物製劑建議治療準則中華民國感染症醫學會（1999. 3. 7） Drug of choice Alternative Community-acquired pneumonia Adults (<60 y) PCN  macrolides Unasyn/Augmentin/2o cephem/FQ/tetracyclines Adults (>60 y) mild-moderate PCN or 2o cephem Unasyn/Aug/FQ  macrolides /tetracyclines severe 3o cephem  AG Timentin/Tazocin/4ocephem  macrolides /FQ  AG  macrolides Aspiration pneumonia PCN or clindamycin Unasyn/Aug/cefoxitin/cef- metazole/PCN+Anergyn Hospital-acquired pneumonia mild-moderate 2o or 3o cephem or Timentin/Tazocin/Azactam/ Unasyn/Aug  AG FQ  AG J Microbiol Immunol Infect 1999; 32: 292-294.

  24. 肺炎抗微生物製劑建議治療準則中華民國感染症醫學會（1999. 3. 7） Drug of choice Alternative Hospital-acquired pneumonia severe 3o cephem or FQ Timentin/Tazocin/Azactam/ + AG 4ocephem/Carbapenem  macrolides + AG  vancomycin  macrolides Ventilator-related pneumonia 3o cephem or FQ Timentin/Tazocin/Azactam/ + AG 4ocephem/Carbapenem  vancomycin + AG  vancomycin FQ: fluoroquinolones, AG: aminoglycosides 「Severe」: ICU, ventilator use, rapid progress, multi-lobar, cavitation or septic shock J Microbiol Immunol Infect 1999; 32: 292-294.

  25. 泌尿道感染抗微生物製劑建議治療準則中華民國感染症醫學會（2000. 3. 11） Drug of choice Alternative Asymptomatic bacteriuria non-pregnant* ─ ─ pregnant 1o or 2o cephem amoxicillin (for enterococci) Acute bacterial cystitis non-pregnant TMP/SMZ, Dolcol FQ, amoxicillin pregnant 1o or 2o cephem amoxicillin Acute uncomplicated pyelonephritis (APN) 1o or 2o cephem ampicillin, AG Acute prostatitis 3ocephem or FQ TMP/SMZ J Microbiol Immunol Infect 2000; 33: 271-272.

  26. 已知可能致病之微生物 • 首選藥物(drug of choice) • 哪些藥物會過敏 • 抗生素對感染部位的藥物穿透力如何，特別針對腦膜炎、骨髓炎、攝護腺炎 • 藥物可能的副作用：如懷孕婦女及兒童避免使用tetracycline及fluoroquinolones藥物 • 抑菌性藥物(bacteriostatic) or 殺菌性藥物(bactericidal) • 降階治療(De-escalating Therapy)

  27. Antibiotics Combination - Synergistic effects

  28. For Drug-resistant GPC • Enterococci or pneumococci • Penicillin + GM • Vancomycin + (? GM) or rifampin • PCN + FQ • MRSA • Vancomycin (or teicoplanain ) + GM or RIF • Linezolid + GM or RIF

  29. For Drug-resistant GNB • for Pseudomonas, drug-resistant E. coli, KP, Proteus… • Prevent emergence of resistant mutant • Anti-pseudomonal b-lactams + GM/AMK • FQs + b-lactams or FQs + carbapenems • FQs + aminoglycosides - still controversial !

  30. for MDR- Stenotrophomonas maltophilia • TMP/ SMX + moxifloxacin or levofloxacin or ciprofloxacin • TMP/ SMX + Ticarcillin/clavulanate ± Aztreonam • meropenem (or imipenem) + sulbactam • meropenem (or imipenem) + amikacin for MDR- Acinetobacter baumannii

  31. 傳染病感染之基本模式 傳染力 致病力 毒力 病原Pathogen 保護力 衛生習慣 疫苗 抗生素 環境消毒 環境Environment 宿主 Host 接觸途徑 接觸機會 接觸量 隔離 洗手

  32. Semmelweis 的故事 A Hungarian gynecologist, trained in Vienna, who demonstrated years before the microbial theory of infection was developed that puerperal sepsis (Gr. A strep) could be prevented by vigorous handwashing.

  33. Impact of Nosocomial Infections on Medical Costs, Hospital Stay, and Outcome Sheng WH, Chie WC, Chen YC, et al. Impact of nosocomial infections on medical costs, hospital stay, and outcome in hospitalized patients. J Formos Med Assoc 2005; 104(5):318-26. Sheng WH, Wang JT, Lu DC, et al. Comparative impact of hospital-acquired infections on medical costs, length of hospital stay and outcome between community hospitals and medical centres. J Hosp Infect 2005;59(3):205-14.

  34. G (+) bacteria- 133 MDR strains: 75% MRSA (37) (MR) S. epidermidis (24) Enterococci (22)… Fungus- 143 C. albicans (78) C. parapsilosis (12) C. glabrata (9) C. tropicalis (8)… 108 (26%) patients had 2 pathogens. 28 (7%) patients had ≥ 3 different pathogens. G (-) bacilli- 317 MDR strains: 77% P. aeruginosa (68) E. coli (60) Enterobacter (49) A. baumannii (43) K. pneumoniae (41)… Anaerobes- 28 Clostridium difficile (12) Bacteroides (12)… None of isolates (26) 院內感染致病菌株MDR- bacteria: resistance ≥ 3 classes of antibiotics

  35. Case group 41 (2-273) days 50.4± 40.1 days ER 0.4 (0-10) ICU 9.2 (0-204) Ward 40.8 (0-273) 平均每一位院內感染發生會延長約 20.1 ±39.3天 (住院日數), 包括 ICU 5.3 ±17.5日, Ward 14.8 ±37.4日. Control group 22 (1-174) days 30.3± 25.3 days (p<0.0001) ER 0.6 (0-8) (p=0.48) ICU 3.9 (0-98) (p<0.0001) Ward 26 (0-174) (p<0.0001) 住院日數 (overall) Sheng WH, et al. J Formos Med Assoc 2005; 104(5):318-26.

  36. 院內感染造成的額外醫療費用 • Extra-costs for every patient with NI: 227774元 • Extra-costs for every episode of NI: 175022元 院內感染額外花費之分布 • 藥劑費 69112元(30%) • 檢驗費(影像醫學檢查費) 29594元(13%) • 診察材料耗品手術費 71475元(31%) • 病房費(護理費) 51776元(23%) • 伙食費 5816元(3%) • Total for NI (case) 227774元 Sheng WH, et al. J Formos Med Assoc 2005; 104(5):318-26.

  37. 不同感染部位之延長住院日數- UTI: 14 (-61 - 174)日- RTI: 17 (-54 - 146)日- BSI: 15 (-61 - 229)日- SSI: 17 (-42 - 233)日 No significant differences (p=0.17)不同感染部位所造成之額外花費- UTI: 297912 (-1229644 - 3408068)元- RTI: 323993 (-1714061 - 2280991)元- BSI: 259934 (-1665174 - 3408068)元- SSI: 206835 (-695872 - 1585872)元 No significant differences (p=0.43)不同感染菌種所造成之花費比較- MRSA 170334 (-194099 - 882955) - E. coli 202001 (-932165 - 2004155) - P. aeruginosa 243173 (-1610684 - 3316250) - Candida albicans 371709 (-901988 - 3408068) NT dollars

  38. 總額給付制度: 院內感染管制十分重要 臺大醫院 (2200病床): 每年約 50,000人次住院; 平均每年約 2,500人次發生院內感染! 每年耗費於院內感染5億7千萬元; 額外住院5萬日! % Overall NI Rate: 4.8% ICU NI Rate: 11% 臺大醫院院內感染發生率

  39. 院內感染在醫學中心比較重要? Nosocomial infection rate in Taiwan • 醫學中心: 4-5% • 區域醫院: 2-4% • 地區醫院: 1-3% • Less disease severity • Lower NI rate • Less resistant bacteria • Lower hospital costs • Less hospitalized days

  40. Demographics of patients : Medical Center - Community Hospitals

  41. Comparisons of Hospital Stay and Costs NT Dollars Sheng WH, et al. J Hosp Infect 2005;59:205-14.

  42. Infection Control for MDR-Bacteria • Periodically surveillance • Evaluate the clinical significance of isolate • Infection control • Contact isolation • Hand washing • Case and nursing care cohorting • Environment decontamination / close ward • Empirical therapy and alternative treatment • ID consultation • Combination for severe or MDR bacterial infection • Mark chart or record to prevent spread • GI tract decolonization (polymyxin for MDRAB)

  43. 洗手標準程序 手沾濕 執行治療或 接觸病人前後 取洗手液 一般洗手用清潔劑 侵入性治療時用消毒劑 雙手搓揉 （注意指尖、指縫） 沖淨後擦乾 搓揉起泡 10-15秒

  44. 洗手前 洗手後

  45. Standard Precautions (標準防護) • Hand washing (洗手) • Gloves (戴手套) • Mask, eye protection, face shield (面罩) • Gown (隔離衣) • Patient-care equipment (醫療器械) • Environmental control (減少環境污染) • Linen (治療巾、床套、被褥) • Occupational health and blood-borne pathogens (血液、體液、痰液等感染檢體處理) • Patient placement (病患之隔離及安置)

  46. 接觸隔離防護(Contact Isolation) • 洗手 • 接觸病患體液、血液、排泄物或污染衣物前後需洗手 • 可帶一般手套,接觸病患及其體液時須戴手套, 手套在照顧病患後需立刻移除後馬上洗手 • 使用一般肥皂洗手即可 • 如有院內抗藥菌流行時,可使用抗菌性肥皂洗手 • 隔離衣(不可重複使用) • 減少病患活動及訪客 • 口罩/面罩/護目鏡 • 口鼻黏膜可能接觸病患體液時(如CPR)需佩戴 • 隔離衣、被單 • 病患照顧器具(包括血壓計等):同一個病患使用一組,避免器械交叉使用 • 環境消毒

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