经验性抗感染治疗方案-药物选择的基本原则和临床实践

1、经验性抗感染治疗方案 -药物选择的基本原则和临床实践抗感染药物发展简史1929 Alexander Fleming 发现青霉素 Howard Florey 和 Ernst Chain分离获得青霉素，用于动物试验。 青霉素首次用于救治战伤患者，拯救了 许多人的生命1950s 大量抗生素用于临床。A poster from World War II, dramatically showing the virtues of the new miracle drug, and representing the high level of motivation in the country to aid

2、 the health of the soldiers at war.Discovery of Antibacterial AgentsCycloserineErythromycinEthionamideIsoniazidMetronidazolePyrazinamideRifamycinTrimethoprimVancomycinVirginiamycinImipenem19301940 195019601970198019902000PenicillinProntosilCephalosporin CEthambutolFusidic acidMupirocinNalidixic acid

3、OxazolidinonesCecropinFluoroquinolonesNewer aminoglycosidesSemi-synthetic penicillins & cephalosporinsNewer carbapenemsTrinemsSynthetic approachesEmpiric screeningNewer macrolides & ketolidesRifampicinRifapentineSemi-synthetic glycopeptidesSemi-synthetic streptograminsNeomycinPolymixinStreptomycinTh

4、iacetazoneChlortetracyclineGlycylcyclinesMinocyclineChloramphenicol“Close the book on infectious disease”“Infectious disease will be with us for the foreseeable future”US Surgeon General William Stewart, 1969Harvard Medical School Mary Wilson, 1998抗生素时代感染仍是人类健康的重要威胁IIIIIIII新出现或“再出现”的感染性疾病 emerging a

5、nd re-emerging infectious diseases新病原体不断出现-HIV/AIDS、Ebola、Hantavirus 新型肝炎、新型克雅病（疯牛病）肠杆菌O157、霍乱O139 环孢子菌病、隐孢子菌病、人类Ehrlichosis老病卷土重来-肺结核、疟疾、鼠疫、霍乱、黄热病、登革热 和登革出血热免疫缺陷人群不断增加-机会性真菌和呼吸道病毒性肺炎细菌耐药愈演愈烈PRSP、MRSP、MRSA/MRSE、VRE、VISA/VERA ESBL、ampC、SSBL、金属酶. MDR结核菌 美国因细菌耐药增加医疗费用超过40亿美元!临床关注的耐药问题Resistances of Cli

6、nical Concerns革兰阳性细菌金匍菌 MRSA, VISA, VRSAVRE (地理上差别)肺炎链球菌 青霉素和喹诺酮耐药 革兰阴性细菌肠杆菌科ESBLs喹诺酮,头孢菌素,青霉素类,氨基糖苷类碳青霉烯类非发酵菌(假单孢菌+/-不动杆菌)喹诺酮, 头孢菌素,青霉素类,氨基糖苷类,碳青霉烯类 Resistant bacteriaMutationsXXAntibiotic resistance: genetic events Susceptible bacteriaResistant bacteriaGene transfer Resistant StrainsRarexxResistan

7、t Strains DominantAntimicrobial Exposure xxxxxxxxxxSelection for Antimicrobial-Resistant Strains抗生素选择压力耐药菌的播散寻找新的抗感染药物 -新药越来越少限制人以外(畜牧业)使用 -减少对人类的影响加强抗感染药物的临床管理 -分级和分线合理使用抗感染药物 加强医院感染的控制 -减少耐药菌株院内传播 细菌耐药的临床对策 -Measures to Resistance减少抗生素选择性压力抗感染药物的临床应用治疗性应用经验治疗 ：因无法确定感染的微生物，推断可能的病原体，参考本地区药敏监测结果，故抗生素

8、必须覆盖所有可能的微生物，常选用联合治疗或单一广谱抗生素治疗性应用目标治疗： 确定了病原体，选用窄谱、低毒性的抗生素预防性应用：Fighting infection in the first hoursRapid testsWhen available. Gram stain! Start adequate antibiotic coverage(within 1 hour?)Tillou A et al. Am Surg 2004;70:841-4Drain purulent collectionSamplingIncluding invasive procedureswhen needed

9、 (BAL)经验性治疗和目标治疗的统一留取标本进行微生物学检查开始经验性抗感染治疗目标治疗Factors Selected by Multivariate Analysis Independently Related to MortalityVariableRelative O.R.p ValueUnderlying disease (UF + RF)3.09.0007Shock2.850.016Bacteremia2.630.019Ineffective Initial Therapy4.71.0001Leroy O Intensive Care Med 1995; 21:24-31Impo

10、rtance of Adequate and Appropriate Antimicrobial TreatmentAdequate antimicrobial treatmentMortalityIncreasedDecreasedInadequate antimicrobial treatmentOngoing bacterial proliferation and inflammationselection of drug-resistant microorganismsEwig et al, Thorax 2002; 57:366Effect of Early Administrati

11、on of Antibiotics on OutcomesHouck PM et al. Arch Intern Med 2004; 164:637-44VariableAll patientsAntibiotics within 4 hoursAntibiotics after 4 hoursAdjusted Odds Ratiop Value30-day mortality12.011.605In-hospital mortality7.05.03% of patients with LOS5 d43.30.00330-day r

12、eadm rate13.45.34Early Administration of Abx significantly decrease mortality and LOSStart empirical antibiotic therapy as soon as possible慢性咳嗽和黄痰-原因哮喘 后鼻腔鼻漏病毒感染后气道高反应性胃酸返流吸烟相关的慢性支气管炎支气管扩张症弥漫性泛细支气管炎肺泡蛋白沉积症急性发热 WBC不高/淋巴增高（无感染灶）病毒！ WBC增高/中性粒增高/核左移 可能细菌！ 部位/病原体？ 原发性菌血症？慢性发热 IE、布病、慢性感染灶？结核病？

13、非感染性发热 药物热、风湿病、恶性肿瘤正确诊断是正确治疗的前提发热的诊断与鉴别诊断Cryptogenic Organizing PneumoniaInfectious Diseases Expert ResourcesInfectious Diseases SpecialistsOptimal Patient CareInfection Control ProfessionalsHealthcare EpidemiologistsClinicalPharmacistsClinical PharmacologistsSurgical InfectionExpertsClinicalMicrobi

14、ologists选择哪种抗菌药物(which antibiotic?) 感染部位的常见病原学(possible pathogens on site of infection) 选择能够覆盖病原体的抗感染药物(antibiotics requirement) -抗菌谱/组织穿透性/耐药性/安全性/费用考虑药代动力学/药效动力学(PK/PD)考虑病人生理和病理生理状态( physiologic and pathophysiology) 高龄/儿童/孕妇/哺乳(advanced age/children/pregnant women/breast feeding) 肾功能不全/肝功能不全/肝肾功能联

15、合不全(renal/heptic dysfunction/combined)其它因素(other considerations) 杀菌和抑菌/单药和联合/静脉和口服/疗程 (cidal vs static/ mono vs combination/ IV vs PO/ duration)经验性抗感染治疗合理选择药物-considerations in choosing antibiotic for empiric therapy 培养结果前依据基本信息选择抗感染药物 choosing Abx before culture result感染部位和可能病原体的关系 association of p

16、athogen with site of infectionGram染色结果-与上述病原体是否符合？ Gram stain-in accordance with suspected pathogen?某些病原体易于造成某些部位的感染 Some pathogen easily cause some site of infection 经验性抗感染治疗药物选择-considerations in choosing antibiotic for empiric therapy 不同感染部位的常见感染性病原体Possible pathogens on site of infection注意特殊修正因子

17、/特别是先期抗菌药物对细菌学的影响 不同感染部位的常见感染性病原体Possible pathogens on site of infection关注特殊病原体肺孢子菌肺炎 -免疫缺陷 -相对特异临床 -积极病原学检查重症军团菌肺炎发热、少痰多肺叶、多肺段受累肺外表现抗菌谱(coverage)通读药物说明书和相关资料组织穿透性(tissue penetration) 抗菌药物的特性（antibiotic itself） 脂溶性(lipid solubility)/分子量(MW) 组织特性（血运/炎症）(tissue itself-blood supply and inflammation) 急性

18、感染/慢性感染(acute vs chronic infection) 细胞内病原体(intra vs extracellullar pathogen) 体内特殊生理屏障(physiologic barriers)-血脑屏障、血胰屏障、胎盘屏障等耐药性(resistance, specifically local resistance) 参考代表性资料/依靠当地资料安全性(safety profile) -药物本身/制剂/工艺/杂质费用/效益(cost/effectiveness) 失败或副作用致再治疗费用更高经验性抗感染治疗药物选能够覆盖可能病原体的抗菌药物（Abx requirements

19、）血脑屏障：多数抗菌药物脑脊液浓度很低脂溶性溶性较高、非极性、蛋白结合率低者易通过血脑屏障炎症时血脑屏障通透性可增加体内特殊生理屏障胎盘屏障：几乎所有抗菌药物都能穿透胎盘屏障进入胚胎循环在妊娠期应避免使用对胎儿发育有影响的抗菌药物 氯霉素、氨基糖苷类、四环素类、磺胺类、氟喹诺酮类、利福平等 抗菌药物在脑脊液中分布 氯霉素青霉素万古霉素链霉素两性霉素B磺胺药氨苄西林阿米卡星庆大霉素林可霉素吡嗪酰胺羧苄西林奈替米星妥布霉素多粘菌素B异烟肼哌拉西林头孢孟多红霉素克林霉素利福平头孢噻肟头孢哌酮苯唑西林乙胺丁醇头孢他啶甲硝唑头孢呋新美洛西林环丙沙星拉氧头孢磷霉素阿昔洛韦亚胺培能阿糖腺苷脑膜炎症或无炎症时

20、csf浓度均可达到抑菌水平（MIC)仅在脑膜炎症时csf浓度均可达到抑菌水平（MIC）脑膜炎症时csf可达一定浓度脑膜炎症时csf浓度仍呈微量者（60 years2.65Diabetes2.57Colodner et al EJCMID 2004 23, 163.Prevalence of rectal carriage of Extended-Spectrum -lactamase -producing Escherichia Coli among elderly people in a community setting in Shenyang 横断面研究/整群抽样-276名社区老人、直肠

21、拭子/大肠杆菌ESBL检测、分子分型和PEGF结果:直肠拭子ESBL+大肠杆菌携带率7.0%（19/270）. 19株ESBL+菌株ESBL基因型均为CTX-M 型 12株为CTX-M-14 型（63.2%), 3株 CTX-M-22型, 1株 CTX-M-24型， 2株 CTX-M-57-like型，1株同时产CTX-M-24和CTX-M-57-like型. 序列分析表明CTX-M-57-like基因序列中第865位点发生GA替换,导致 氨基酸序列中第289位点发生DN替换,该基因序列不同于 GenBank数 据库已发表序列，提示新型ESBLs基因型(GenBank 序列号 EF426798

22、) Tian SF, Chen BY.Prevalence of rectal carriage of Extended-Spectrum -lactamase -producing Escherichia Coli among elderly people in a community setting in Shenyang, China. Canadian Journal of microbiology 2008;54:1519株产ESBLs的大肠埃希菌的PFGE图谱左起依次为：Marker，菌株编号T2-S28.产ESBLs菌株PFGE图谱呈多样性，提示社区产ESBLs的大肠埃希菌为多克

23、隆起源 Univariate analysis of risk factors for carriage of ESBL-producing Escherichia coli in the community (n=270)Potential Risk factors No(%) ESBLs Total No Odds ratio(95% CI) P value Age (years) 74 16(7.4) 216 75 3(5.6) 54 0.74(0.21-2.62) 0.77 Gender Female 12(7.8) 153 Male 7(6.0) 117 0.81 (0.31-2.1

24、3) 0.81 Diabetes No 11(6.3) 174 Yes 8(8.3) 96 1.35(0.52-3.47) 0.62 Hospitalization in past one year No 18(6.8) 264 Yes 1(16.7) 6 2.73(0.30-24.66) 0.34 Surgery in past one year No 19(7.1) 268 Yes 0(0) 2 0.0 0.8 Use of antibiotic in past three months No 12(5.3) 227 Yes 7(16.3) 43 3.48(1.29-9.44) .018产

25、ESBL细菌感染的危险因素Prospective study of 455 episodes of K. pneumoniae bacteremia (253 nosocomial) in 12 hospitals30.8% 为医院获得, ICU中43.5%产ESBLsESBLs危险因素 先期使用氧亚氨基-内酰胺类抗菌药物 过去14天内使用2 d (OR= 3.9). 其它危险因素 TPN, 肾功衰竭,烧伤非ESBL危险:碳青霉烯、头孢吡肟、喹诺酮、氨基糖苷类 Paterson et al: Ann Intern Med 2004; 140:26-32.VAP耐药菌感染的危险因素135 次VA

26、P ICU变量 OR PMV7 days 6.0 .009先期ABs 13.5 7 days / prior ABsTrouillet, et al. Am J Respir Crit Care Med. 1998;157:531Trouillet JL et al. Clin Infect Dis. 2002;34:1047-1054.铜绿VAP: 34株派拉西林耐药; 101株派拉西林敏感发生VAP15天内使用抗菌药（亚胺培南, 3代头孢和喹诺酮)增加铜绿对同种药物的耐药性aP=.0009 bP=.003 cP=.001 dP=.05Resistance of P aeruginosa S

27、trains To Imipenem, Ceftazidime, or Ciprofloxacin, According to Previous Therapy With Imipenem, a 3rd-generation Cephalosporin, or a FluoroquinoloneNo. (%) of patients, by previous drug therapy receivedImipenemThird-generation cephalosporinFluoroquinoloneStrain resistanceNo(n=114)Yes(n=21)No(n=73)Ye

28、s(n=62)No(n=100)Yes(n=35)To imipenem19 (16.7)11 (52.4)a12 (16.4)18 (29.0)18 (18)12 (34.3)dTo ceftazidime17 (14.9)7 (33.3)6 (8.2)18 (29.0)b14 (14)10 (28.6)To ciprofloxacin35 (30.7)11 (52.4)25 (34.2)21 (33.9)26 (26)20 (57.1)c关注耐药病原体-近期应用抗菌药物与铜绿耐药S. aureusPenicillin1944Penicillin-resistantS. aureus金黄色葡

29、萄球菌耐药的发生发展过程Methicillin1962Methicillin-resistantS. aureus (MRSA)Vancomycin-resistantenterococci (VRE)Vancomycin1990s1997VancomycinintermediateS. aureus(VISA)2002Vancomycin-resistantS. aureusCDC, MMWR 2002;51(26):565-5671960Macrolide resistant S. pneumoniae in Asian Countries: ANSORP 1998-2001- 555 i

30、solates- macrolide susceptibility- 216 S (38.9%)- 10 I (1.8%)- 329 R (59.3%)Vietnam88.3% RHong Kong 76.5% RTaiwan87.2% RChina75.6% RKorea85.1% R- ermB more common (50%) China, Taiwan, Sri Lanka, Korea.- mefA more common Hong Kong, Singapore, Thailand, Malaysia.- most countries MIC90 12 mg/L.Song et

31、al, Journal of Antimicrobial Chemotherapy 2004; 53(3):457-463.红霉素耐药肺炎链球菌表型和基因型;43(5):329-332/AAC,2004;48（10）:4040-4041耐药表型基因型N=148抗菌谱(coverage)通读药物说明书和相关资料组织穿透性(tissue penetration) 抗菌药物的特性（antibiotic itself） 脂溶性(lipid solubility)/分子量(MW) 组织特性（血运/炎症）(tissue itself-blood supply and inflammation) 急性感染/

32、慢性感染(acute vs chronic infection) 细胞内病原体(intra vs extracellullar pathogen) 体内特殊生理屏障(physiologic barriers)-血脑屏障、血胰屏障、胎盘屏障等耐药性(resistance, specifically local resistance) 参考代表性资料/依靠当地资料安全性(safety profile) -药物本身/制剂/工艺/杂质费用/效益(cost/effectiveness) 失败或副作用致再治疗费用更高经验性抗感染治疗药物选能够覆盖可能病原体的抗菌药物（Abx requirements）评估

33、责任病原体评估病原体耐药性Avoiding the adverse outcomes of resistanceindividual patient perspective应用耐药可能性低的药物到位！ 治疗决定个体化耐药的可能性？病人的致病微生物？ 病人来源? 选择压力用当地的监测资料不越位！耐药交叉耐药资料选择哪种抗菌药物(which antibiotic?) 感染部位的常见病原学(possible pathogens on site of infection) 能够覆盖病原体的抗感染药物(antibiotics requirement) 抗菌谱coverage)/组织穿透性(tissue

34、penetration) /耐药性(resistance pattern) /安全性(safety)/费用(cost)优化药代动力学/药效动力学(optimizing PK/PD)考虑病人生理和病理生理状态( physiologic and pathophysiology) 高龄/儿童/孕妇/哺乳(advanced age/children/pregnant women/breast feeding) 肾功能不全/肝功能不全/肝肾功能联合不全(renal/heptic dysfunction/combined)其它因素(other considerations) 杀菌和抑菌/单药和联合/静脉和

35、口服/疗程 合理的经验性抗感染治疗药物选择 considerations in choosing antibiotic for empiric therapyPharmacology of Antimicrobial TherapyDosingregimenConcentrationsin serumConcentrationsin tissues and body fluidsConcentrationsat site of infectionPharmacologic and toxicologic effectAntimicrobialeffectAbsorptionDistributi

36、onEliminationPharmacokinetics (PK)Pharmacodynamics (PD)MIC、 MBCDifferent pattern of time-killing of 3 Abx VS PseudomonasKilling and rate of killing depends on concentrationRate of killing increases no more as concentration increases, killing depends on exposure timePK/PD Predictors of Efficacy-a com

37、bination of PK and PDTimeMIC90Log Concentration24h-AUCT MICCmax, Cmax/MIC24h-AUC/MIC (AUIC)DoseDoseCmaxTMICParameters of interestPK/PD Predictors of Efficacy依据PK/PD抗菌药物分类时间依赖性与时间有关，但抗菌活性持续时间较长对致病菌的杀菌作用取决于峰浓度抗菌作用与同细菌接触时间密切相关时间依赖且PAE或T1/2较长 氨基糖苷类、氟喹诺酮类、酮内酯类、两性霉素B、 daptomycin、甲硝唑多数-内酰胺类、林可霉素类恶唑烷酮类、氟胞嘧啶

38、 链阳霉素、四环素、碳青霉烯类、糖肽类、大环内酯类、唑类抗真菌药 主要参数AUC0-24/MIC(AUIC)Cmax/MIC 主要参数 TMIC和AUCMIC主要参数 TMIC, PAE，T1/2 AUC/MIC 浓度依赖性Required %TMIC for cidal: 40% for carbapenems 50% for penicillins 70% for cephalosporinsDrusano GL. Clin Infect Dis. 2003;36(suppl 1):S42-S50. Required %TMIC for static 20% for carbapenems

39、 30% for penicillins 40% for cephalosporins -lactam:optimal TMIC?Drusano. Clin Infect Dis 2003;36(Suppl. 1):S42S50Maximizing TMIC提高剂量安全性前体增加给药频率延长输注时间 -内酰胺类优化暴露时间-Lactam: Optimizing ExposureDandekar PK et al. Pharmacotherapy. 2003;23:988-991.Meropenem 500 mg Administered as a 0.5 h or 3 h InfusionMI

40、C02468Concentration(mcg/mL)Time (h)Rapid Infusion (30 min)Extended Infusion (3 h)Treatment of Multidrug-resistant Burkholderia cepacia With Prolonged Infusion MeropenemMeropenem 2 g infused over 3 hours q 8 hTime (h)Concentration (mcg/mL)0816243240110100MIC = 16 mcg/mLTMIC exposure was 40% of the do

41、sing interval at the MIC of16 mcg/mLKuti JL et al. Pharmacotherapy. 2004;24:1641-1645Moore et al. J Infect Dis 1987;155:9399Aminoglycoside:optimal Cmax:MIC -Relationship Between Cmax:MIC and Clinical ResponseClinical response (%)Cmax :MIC02040608010024681012556570838992What is the Optimal AUIC for F

42、luoroquinolones?30125For G+For G-Forrest et al. Antimicrob Agents Chemother 1993;37:10731081Fluoroquinolone Therapy for Nosocomial Pneumonia Correlation Between Drug Exposure (AUC/MIC) & OutcomePatients cured (%)0204060801000125125250250500500AUC:MICClinicalMicrobiologicalAUC:MIC125 lead to appropri

43、ate clinical and microbiological outcomeGram-Negative Bacterial Eradication and Fluoroquinolone AUICDays 0 2 4 6 8 10 12 140100755025AUIC 125-250AUIC 250AUIC 125% Patients remaining culture positiveForrest et al. Antimicrob Agents Chemother. 1993;37:1073-1081Higher AUC:MIClead to letter bacterial er

44、adicationProbability of Developing ResistanceThomas KL et al. Antimicrob Agents Chemother. 1998;42:521527AUC024h:MIC 100AUC024h:MIC 100 Free AUIC 30-40Resistance preventionCmax MPCHigher AUICBaquero & Negri. BioEssays 1997; 19: 731-6 Drlica K. ASM News 2001; 67:27-33Cantn et al. Inter J Antimicrob C

45、hemother 2006 (in press)Concentration (g/ml)Time post administration (h)CmaxMPCTmax MICWindow of selectionMICMPC(MIC of mutants)Resistant mutantSusceptible bacteria选择哪种抗菌药物(which antibiotic?) 感染部位的常见病原学(possible pathogens on site of infection) 能够覆盖病原体的抗感染药物(antibiotics requirement) 抗菌谱coverage)/组织穿透

46、性(tissue penetration) /耐药性(resistance pattern) /安全性(safety)/费用(cost)优化药代动力学/药效动力学(optimizing PK/PD)考虑病人生理和病理生理状态( physiologic and pathophysiology) 高龄/儿童/孕妇/哺乳(advanced age/children/pregnant women/breast feeding) 肾功能不全/肝功能不全/肝肾功能联合不全(renal/heptic dysfunction/combined)其它因素(other considerations) 杀菌和抑菌/

47、单药和联合/静脉和口服/疗程 合理的经验性抗感染治疗药物选择 considerations in choosing antibiotic for empiric therapy老人感染特点易发生细菌感染常见肺炎、尿感、胆道感染、败血症常见菌:G-杆、金葡、肺球、肠球、真菌老人抗菌药药理肾功减退，半减期长，血浓度高肝解毒功能降低组织退化、防御功能低，胃、尿、胆汁中常有菌水量减少，药物在脂肪中浓度高白蛋白减少，游离药物多老人抗菌治疗宜用杀菌剂避免肾毒性药物有条件的做TDM(特别用肾毒性药物时)不良反应多，且不易发现肝肾清除减退剂量宜低、分次给药注意全身状态心功能、水盐平衡小儿抗菌药药理药物酶系不成

48、熟，血浓度偏高肾发育不全，药物排泄减少胞外溶液量大，药物消除慢与血浆蛋白结合松，游离药物多小儿抗菌治疗剂量宜低避免应用毒性明显的药物：氨基糖甙、多粘、磺胺、呋喃、喹诺酮避免肌注血容积大，肾血流量大，分布容积大剂量宜增，对药物毒性敏感药物通过胎盘，影响胎儿孕妇抗菌药药理药物可自乳汁分泌，无论乳汁中药物浓度如何，均存在对乳儿潜在的影响，并可能出现不良反应哺乳期应用任何抗菌药物时，均宜暂停哺乳乳汁中含量较高喹诺酮、四环素类、大环内酯类、氯霉素、磺胺、甲氧苄啶、甲硝唑、异菸肼、乳汁含量较低青霉素类、头孢菌素类、氨基糖苷类哺乳期患者抗菌药物的应用抗微生物药在妊娠期应用时的危险性分类FDA分类 抗微生物药

49、A. 在孕妇中研究证实无危险性B. 动物中研究无危险性，但人类 研究资料不充分，或对动物有 毒性，但人类研究无危险性青霉素类头孢菌素类青霉抑制剂氨曲南美罗培南厄他培南红霉素阿奇霉素克林霉素磷霉素两性霉素B特比奈芬利福布丁乙胺丁醇甲硝唑呋喃妥因C. 动物研究显示毒性，人体研究 资料不充分，但用药时可能患 者的受益大于危险性亚胺培南氯霉素克拉霉素万古霉素氟康唑伊曲康唑酮康唑氟胞嘧啶磺胺药氟喹诺酮利奈唑胺乙胺嘧啶利福平异烟肼吡嗪酰胺D. 已证实对人类有危险性，但仍 可能受益多氨基糖苷类 四环素类X. 对人类致畸，危险性大于受益 奎宁 乙酰异烟胺 利巴韦林哺乳期患者抗菌药物的应用药物可自乳汁分泌，无论

50、乳汁中药物浓度如何，均存在对乳儿潜在的影响，并可能出现不良反应哺乳期应用任何抗菌药物时，均宜暂停哺乳乳汁中含量较高喹诺酮、四环素类、大环内酯类、氯霉素、磺胺、甲氧苄啶、甲硝唑、异菸肼、乳汁含量较低青霉素类、头孢菌素类、氨基糖苷类肾功能不全/肝功能不全/肝肾功能联合不全肝功严重不全：将肝排泄抗生素减量50 换用以肾脏失活或者排泄为主的药物肾 功 不 全：CCr40-69ml/min-减少肾排泄药物剂量50，间隔不变 CCr10-40ml/min-减少肾排泄药物剂量50，双倍间隔 换用肝脏失活或者排泄的药物联 合 不 全：无合宜建议。平衡两者病变的程度注意:老年人血肌酐正常不代表肾功能正常！肝功能

51、减退时抗菌药物的应用药物对肝脏的作用肝病时应用大环内酯类自肝胆系统清除减少；按原量慎用减量应用，酯化物具肝毒性避免应用其酯化物林可类半减期延长，清除减少转氨酶增高减量慎用氯霉素在肝内代谢减少，血液系毒性避免使用利福平可致肝毒性，可与胆红素竞争酶结合致 避免使用，尤应高胆红血症避免与异烟肼同用异烟肼乙酰肼清除减少，具肝毒性避免使用或慎用两性B肝毒性、黄疸禁用四，土严重肝脂肪变性避免使用磺胺肝内代谢，与胆红素竞争血浆蛋白结合， 避免使用引起高胆红素血症酮康唑、咪康唑肝内代谢灭活，肝病时灭活减少避免使用，或监测血药浓度慎用哌拉、阿洛肾、肝清除，肝病时清除减少严重肝病时间减量慎用噻肟、噻吩肾、肝清除，

52、严重肝病清除减少严重肝病时间减量使用肝功能减退时适用的抗菌药-内酰胺类多粘菌类氨基糖苷类磷霉素万古霉素类 莫西沙星（child A/B）肾功能损伤者感染时抗菌药物的选用可选用，按原治疗量或略减量 莫西沙星，红霉素、利福平、多西环素、克林霉素、氨苄西林、阿莫、哌拉西林、 美洛西林、苯唑西林、头孢哌酮、头孢曲松、头孢噻肟、氯霉素、两性霉素B、异烟肼、 乙胺丁醇、甲硝唑、酮康唑可选用，剂量需中等度减少者 青霉素、羧苄西林、阿洛西林、头孢唑啉、头孢噻吩、头孢氨苄、头孢拉定、头孢孟多、头孢西丁、头孢呋辛、头孢他啶、头孢唑肟、拉氧头孢、头孢吡肟、氨曲南、亚胺培南、SMZ+TMP*避免应用，确有指征应用时在

53、血药浓度监测下显著减量应用庆大霉素、妥布霉素、奈替米星、阿米卡星、卡那霉素、链霉素等氨基糖苷类、万古霉素、壁霉素、氟胞嘧啶不宜用者四环素类*、呋喃妥因、萘啶酸*在血药浓度监测条件下应用*除多西环素外选择哪种抗菌药物(which antibiotic?) 感染部位的常见病原学(possible pathogens on site of infection) 能够覆盖病原体的抗感染药物(antibiotics requirement) 抗菌谱coverage)/组织穿透性(tissue penetration) /耐药性(resistance pattern) /安全性(safety)/费用(co

54、st)优化药代动力学/药效动力学(optimizing PK/PD)考虑病人生理和病理生理状态( physiologic and pathophysiology) 高龄/儿童/孕妇/哺乳(advanced age/children/pregnant women/breast feeding) 肾功能不全/肝功能不全/肝肾功能联合不全(renal/heptic dysfunction/combined)其它因素(other considerations) 杀菌和抑菌/单药和联合/静脉和口服/疗程 合理的经验性抗感染治疗药物选择 considerations in choosing antibio

55、tic for empiric therapy选择抗菌药物时应考虑的其它因素 Other considerations in choosing Abx 杀菌 vs 抑菌(Cidal vs static) 严重/复杂感染选杀菌剂 cidal for serious and compicated infections单药 vs 联合(monotherapy vs combination)：静脉 vs 口服(IV vs oral)疗程(duration)联合用药的理由补充单一用药的抗菌谱不足！协同作用铜绿假单孢菌菌血症减少耐药？2007 ATS/IDSA Guidelines: Inpatients

56、Mandell LA, et al. Clin Infect Dis 2007CAP Inpatient TherapyMedical WardIntensive Care UnitRecentAntibioticNo RecentAntibioticRespiratory FQ alone ORAdvanced macrolide + -lactamNo Pseudomonas RiskNo -lactam Allergy-lactam Allergy-lactam + advanced macrolide OR + respiratory FQ* Regimen depend on nature of recent Abx therapyRespiratory FQ + aztreonamPseudomonas RiskNo -lactam Allergy-lactam Allergy Anti-pseudomonal, antipneumococcal b- lactam /penem + Cipro/Levo 750 OR Anti-pseudomonal,