课件：危重感染抗菌药应用.ppt

Dose Optimization of Antimicrobial Agents in Patients with Severe Infection,First Affiliated Hospital of Medical College of XiAn JiaoTong University Dept of Critical Care Medicine Wang, Xue,Therapeutic Strategy of Antibiotic to Severe Infection,Therapeutic Strategy of Antibiotic to Patients with Severe Infection,Initial empirical therapy VS. Targeted therapy Down-ladder therapeutic strategy:is a anti-infective protocol of empirical therapy has two characteristics as following: use a single, broad-spectrum, potent antibiotic at the beginning of anti- infective therapy, try to cover the pathogenic bacteria; afterward (48 to 72 hours), based on microbiological and susceptibility tests to adjust the antibiotics, let it more specific Adapted to Down-ladder therapy program: severe pneumonia presence of risk factors (received antibiotic treatment, length of hospital stay, mechanical ventilation) drug selection should aim to suspected pathogen,Appropriate treatment: Bacterial sensitivity to antibiotics matchs selected antimicrobial agents,ATS/IDSA Guidelines. Am J Respir Crit Care Med. 2005;171:388-416.,“S” = success,Therapeutic Strategy of Antibiotic to Patients with Severe Infection,Therapeutic Strategy of Antibiotic to Patients with Severe Infection,Initial empirical therapy Down-ladder therapeutic strategy Targeted therapy Adequate antibiotic therapy,Inadequate antimicrobial treatment was correlated with high mortality in severe infection,三项对ICU感染患者起始抗菌治疗的前瞻性研究，结果表明重症患者感染起始不充分抗菌治疗显著增加患者住院死亡率,Blood flow infection,NP/VAP,Ibrahim EH et al. Chest. 2000;118:146-155. Alvarez-Lerma F et al. Intensive Care Med. 1996;22:387-394. Rello J et al. Am J Respir Crit Care Med. 1997;156:196-200.,1,P 0.001,P = 0.034,P 0.05,Mortality (%),Inadequate,adequate,Inadequate antimicrobial treatment significantly affects the survival rate of patients with severe infection,A retrospective study analyzed the data of 5715 cases with septic shock from three countries and found that early inadequate empirical antimicrobial therapy significantly reduced the survival rate in patients with various severe bacterial infection,Staphylococcus aureus Streptococcus pneumoniae Enterococcus Other Streptococcus E. coli Klebsiella spp. Enterobacter Pseudomonas aeruginosa Candida albicans Non-white yeast,Kumar A et al. Chest 2009;136:1237-48.,All patients Culture（+） Culture（-） Bacteremia（+） Bacteremia（-） Community-acquired infections Hospital-acquired infections,Early inadequate treatment Early adequate treatment,Survival rate（%）,Odds ratio（OR）,Early inadequate treatment Early adequate treatment,Survival rate（%）,Odds ratio（OR）,上述决定因素取决于： 体外效力（微生物特性） 药物暴露（药物代谢动力学特性） 体内效力（药效学特性）,Adequate Antibiotic Therapy,临床和微生物学治疗成功的决定因素,Adequate antibiotic therapy should regard patients as a “core”: Considering the relationship among the “patients- drugs - bacteria“ comprehensively,PATIENT,PATHOGENIC BACTERIA,ANTIMICROBIAL AGENTS,Resistance to disease (immunity),Pathogenicity,in vivo metabolism（PK）,Adverse reactions,Drug resistance (MIC),Antibacterial effect (PD),Alteration of Pharmacokinetics in Severe Infection,Severe infection = Sepsis + acute organs dysfunction,Characteristics of Severe Infection,Basic status, complex and dangerous Presence of multiple diseases or organ failure Changes of drug distribution and metabolic processes in the body Use several drugs and therapeutic measures simultaneously Prone to occurring drug interactions or adverse reactions,Drug,Plasma Protein-binding drugs Free drug Metabolites,Renal excretion,Site of action Free drug Receptor binding Pharmacological effect,Organ storage Free drug Tissue binding,Liver Metabolites,Absorption,Re-absorption,Metabolic process of drug in vivo,Capillary leakage,Hypoproteinemia,Tissue ischemia and hypoxia,Organ dysfunction,Drug intake,Concentration of drug in blood circulation system,Distribution of drug in tissueC,Concentration of drug at active site,Pharmacological effect,Clinical reactive effect,Toxicity,Therapeutic effect,（PK）,（PD）,absorption,Distribution,Clearance,Metabolism or excre tion of drugC,Effect of severe infective patient to PK,Hypo-albuminemia: protein binding capacity CLS: increased volume of distribution CRRT: clearance increase MODS: toxic-side effects,Enhancement of distribution volume (Vd) of antimicrobial drugs in severe patient,A total of 57 items of PK / PD study for beta-lactam antimicrobial agents in ICU patients during1966-2010 was systematic reviewed; Results showed that the volume of distribution (Vd) of six antimicrobial agents in critical patients were significant increased compared to the healthy volunteers.,Joao Goncalves-Pereira ,et al.Critical Care 2011, 15:R206,healthy volunteer,ICU patient,Cefpirome,Cefepime,Ceftazidime,Piperacillin,Imipenem,Meropenem,Volume of Distributionf (L),Increased volume of distribution (Vd) in critical patient Drug concentration reduced in blood and tissue,The systemic inflammatory response and alteration of vascular permeability in patients with severe infection resulted to hypotension and exudation of capillary fluid Meantime, a plenty of liquid infusion for anti -hypotension and anti-septic shock clinically also increased the volume of distribution,Ulldemolins M, Rello J. Curr Pharm Biotechnol. 2011;12(12):1996-2001.,Vp: volume of distribution in peripheral room (organs) ; Vc: volume of distribution in central compartment (plasma),Healthy volunteer,ICU patient,标准药物剂量,标准药物剂量,Volume of distribution of Amikacin in 100 ICU adults and children Result Vd was increased in accordance with the severity of disease Vd was increased in all water-soluble antibiotics in ICU, the initial dose should be higher than the standard one!,Marik et al JAC 1991;27 Supp C:81-9,Volume of distribution (Vd) of antibiotics vs. disease severity,Alteration of different physical and chemical properties and PK in severe infection,Crit Care Med 2009; 37(3): 840-51,Common PK,Low Vd Clearance by kidney mainly Low cell penetrating,High Vd Clearance by liver mainly Better cell penetrating,Change of ICU PK,Determined by liver function,Determined by renal function,Example,Beta-Lactams Aminoglycosides Glycopeptides Linezolid Polymxin,Fluroquinolones Macrolides Lincosamides Tigecycline,Water-soluble antibiotics,Fat-soluble antibiotics,Data submitted,Antibiotics Vd - protein binding capacity in severe infection,High binding Very important ! Moderate Moderate Combination very low combination not so important,For drugs with high protein binding, hypoproteinemia -induced decline of binding capacity is very important! May result in increased toxicity or clearance TDM is not up to standard range,PK / PD is changed by sepsis,Extracorporeal circulation,Change of drug clearance and enhancement of Vd in ARF,? Plasma drug concentration,If the dose is not adjusted correspondingly: it is NOT the best therapy (incomplete treatment),Non-optimal clinical outcome,Capillary leakage and/or change of protein binding capacity,Sepsis,Cardiac output increased,Increased clearance rate,increased apparent Vd,Low plasma drug concentration,Normal organ functions,unchanged apparent Vd,Normal plasma concentration,End-stage organ function failure(Kidney Liver),Reduced clearance rate,High plasma drug concentration,Optimization of antibiotic dosage in severe infection,The relationship of medicine - time curve and drug concentration and therapeutic effect,Time(h),Cmax Peak,Minimal inhibitory concentration(MIC90 value),Time of effective concentration maintain,AUC,Average plasma concentration,(mg/L),Toxic concentratin,Therapeutic scope(treatingwindow,Time to maximal concentration tmax,Interaction strength,Evaluation parameters of PK / PD for antimicrobial agents,AUC：The area under the concentration-time curve;Cmax :Peak plasma concentration;PAE:Post-antibiotic effect,0,Cmax:MIC,Drug concentration,Time (h),MIC,Concentration- dependent,Time-dependent,Potent of antibiotic effect,Pharmacodynamics (PD) Index of antibiotics,Concentration-dependent ( with prolong and constant bactericidal effect) Time-dependent ( without prolong and constant bactericidal effect) Time-dependent (Moderate prolong and constant bactericidal effect),Aminoglycosides Quinolones Relate to AUC/MIC, Peak/MIC Beta-Lactams Relate to time above MIC (TMIC) Macrolides ,Aza-lactone ,glycopeptides Oxazolidinone ,Tetrcyclines, Clindamycin Relate to AUC/MIC,Crit Care Med 2009; 37(3): 840-51,T 40-70% 4-5xMIC,Cmax:MIC =10,Van:400 Quinolone:G-:125 G+:30,Pharmacodynamics (PD) Index of antibiotics,14例入组ICU的VAP（临床肺部感染评分【CPIS】 6 ）患者 左氧氟沙星： 第1天2500mg；随后连续7天1500mg 通过中心静脉管静脉输注，60分钟内输完 左氧氟沙星PK/PD指数： f Cmax,ss/MIC; f AUC/MIC,氟喹诺酮类： 格兰阴性菌：f Cmax,ss/MIC = 10; f AUC/MIC 100125 格兰阳性菌：f Cmax,ss/MIC = 10; f AUC/MIC 30,Cases,Case (Meropenem 1g q8h 30 min Infusion),The PD of Tigecycline and dose optimization,61例院内获得性肺炎患者使用替加环素 静脉输注100 mg负荷剂量 之前输注剂量为50 mg q12 h 至少持续输注7天,结果： 临床成功率： 白蛋白每升高1g/dl，成功率升高13.0倍（P 0.9的患者则升高8.42倍（P =0.008）,结果： 微生物学成功率 白蛋白每升高1g/dl，成功率21.0倍（P 0.001） 非VAP相比VAP，前者成功率高8.59倍（P= 0.003） MIC：（P=0.006） MIC50：VAP vs 非VAP 0.5 vs 0.25 mg/l MIC90：VAP vs 非VAP 16 vs 1 mg/l,替加环素的MIC分布由是否VAP状态来区分,Clinical and microbiological efficacy of Tigecycline to cIAI patients: AUC/MIC6.96,Combined analysis of 3 clinical studies of Tigecycline to hospitalized c1A1 patients was performed, the results showed that in patients with E. coli and anaerobic infection, the AUC / MIC 6.96 can ensure the high curative rates both in clinical and microbiological aspects,Passarell JA, et al. Antimicrob Agents Chemother. 2008;52(1):204-210. Ambrose PG, et al. Diagn Microbiol Infect Dis. 2009;63(1):38-42.,AUC/MIC6.96can ensure he high cure rate1 microbiological cure (P=0.0004) Clinical recovery(P=0.0399),AUC/MIC6.96， Clinical curative rate 94% AUC/MIC6.96，Clinical curative rate 60% （P=0.0399)2,Queue 1: E. coli; Queue 2: single or multiple E.coli; Queue 3: at least one kind E.coli + anaerobes; Queue 4: at least one E.coil + G+- bacteria,Combined analysis of Tigecycline to cSSSI patients in one clinical Phase II and two Phase III studies was conducted, the results disclosed that in patients with staphylococcus aureus or streptoco-ccus viridans infection:,Meagher AK, et al. Antimicrob Agents Chemother. 2007;51(6):1939-1945. Ambrose PG, et al. Diagn Microbiol Infect Dis. 2009;63(2):155-159.,Queue 1: Staphylococcus aureus; Queue 2: single Staph.aureus or viridans strepto.; Queue 3: Two G+- bacteria; Queue 4: Multiple bacterial infection; Queue 5: other single bacterial infection,Clinical and microbiological efficacy of Tigecycline to cSSSI patients: AUC/MIC17.9,AUC/MIC17.9 can ensure the high curative rate1 Microbiological cure (P=0.0001) clinical recovery (P=0.0376),AUC/MIC17.9，microbiological cure100% AUC/MIC17.9，clinical recovery50% (P=0.0001)2,The AUC / MIC of Tigecycline achieved to standard level: Better clinical efficacy,Combined analysis of Tigecycline to hospitalized cIAI patients in two Phase III studies was performed. The results showed that in the E. coli-infected patients, when MIC 0.5 mg / L, the rate of PK / PD achieved to standard level was over 90%,In 2009, a survey of drug- resistance of pathogenic bacteria among patients with hospital-infection in a total of 13 teaching hospitals in China indicated that E. coli to Tigecycline : MIC50=0.25 mg/L MIC90=0.5 mg/L,MIC=0.25 mg/L:clinical recovery94% MIC=0.5 mg/L: clinical recovery84%,Ambrose PG, et al. Diagn Microbiol Infect Dis. 2009;63(2):155-159. Yangqiwen, etc Chinese Journal of Laboratory edicine.2011;05(34):422-430.,Pooled analysis of Tigecycline to cSSSI patients in one phase II and two Phase III clinical studies was performed. Data revealed that in patients with Staphylococcus aureus or Streptococcus viridans infection, when MIC 0.25 mg / L, the rate of PK / PD achieved to standard range was 60 to 100%.,Ambrose PG, et al. Diagn Microbiol Infect Dis. 2009;63(2):155-159. Yangqiwen, etc Chinese Journal of Laboratory edicine.2011;05(34):422-430.,In 2009, a survey of drug- resistance of pathogenic bacteria among patients with hospital-infection in a total of 13 teaching hospitals in China revealed that Staphylococcus aureus to Tigecycline: MIC50=0.125 mg/L，MIC90=0.25 mg/L Streptococcus viridans to Tigecycline: MIC50=0.064 mg/L，MIC90=0.25 mg/L,The AUC / MIC of Tigecycline achieved to standard level: Better clinical efficacy,MIC=0.125 mg/L:clinical cure rate 99.9% MIC=0.5 mg/L:clinical cure rate 94.2%,Tigecycline vs Imipenem Hospital-acquired pneumonia (HAP) phase III registration study,Phase III, international multi-center, double-blind, randomized, controlled, non-inferiority clinical screened a total of 138 research centers in 31 countries with 979 HAP or VAP patients: 945 cases in the randomized (ITT population), 934 cases treated (safety population, mlTT population ) At the end of study, 531 cases for microbiologic evaluation and 511 patients for clinical assessment,TOC follow up,Tigecycline first dose 100 mg， followed by 50 mg q12h i.v.,If pseudomonas aeruginosa or MRSA infection can not be excluded : In order to cover pseudomonas aeruginosa, all groups of Tigecycline treatment received adjuvant therapy: ceftazidime 2 g q8h In order to cover MRSA, the group of imipenem / cilastatin treatment received adjuvant therapy: vancomycin 1g q12h,EOT: End of the treatment；TOC：Cure the check,Freire AT, et al. Diagn Microbiol Infect Dis. 2010;68(2):140-151.,Therapeutic course 7-14 day,EOT after10-21day,1:1 Randomized,Imipenem / cilastatin 1 g q8h i.v.,In TOC, the cure rate of tigecycline group in non-VAP patients was fulfilled together with imipenem / cilastatin non-inferiority resistance ; non-inferiority is not reached in patients with VAP,35/73,147/195,Cure rate （%）,Difference between -22.2 95%CI (-37.8, -4.9),Freire AT, et al. Diagn Microbiol Infect Dis. 2010;68(2):140-151.,Clinical evaluable population,c-mITT population,Difference between-5.9 95%CI (-14.5, 3.0),Difference between-11.3 95%CI (-24.6, 2.0),Difference between-1.9 95%CI (-9.4, 5.6),47/67,143/176,59/127,217/313,67/116,223/313,Non-inferiority is not reached,Non-inferiority reached,c-Mitt population: Intentional treating population by clinical correction,Tigecycline vs. Imipenem Hospital-acquired pneumonia (HAP) phase III registration study,Tigecycline 50 mg q 12h,Non-VAP,Non-VAP,Non-inferiority reached,Non-inferiority is not reached,The prominent different of PD in Non-VAP and VAP patients,Freire AT, et al. Diagn Microbiol Infect Dis. 2010;68(2):140-151.,Non-VAP patients AUC0-12h=3.198,VAP patients AUC0-12h=2.726,15%significantly decline （P=0.041）,显著降低60% （P=0.002）,AUC0-12h,AUC0-24h/MIC,Tigecycline vs. Imipenem Hospital-acquired pneumonia (HAP) phase III registration study,Non-VAP patients AUC0-12h=3.198,Non-VAP,Bhavnani SM, et al. Antimicrob Agents Chemother. 2012;56(2):1065-1072.,Prescribed dose PD of Tigecycline affected efficacy in patients with VAP,The microbiological cure rate in Non-VAP patients may be 8.59 times higher than those in VAP patients （P=0.003）,Bhavnani SM, et al. Antimicrob Agents Chemother. 2012;56(2):1065-1072.,Enhancement of clinical cure rate of Tigecycline： PD：AUC/MIC0.90/ Serum albumin concentration 26g/L,AUC0-24h/MIC0.90较 0.9 clinical cure rate may increase 8.42times （P=0.008）,AUC0-24h/MIC0.90,AUC0-24h/MIC0.90,Serum albumin concentration elevates 1g/dL, clinical cure rate may increase 13.0 times （P0.001）,Clinical cure rate,Albumin,Treatment of HAP by Tigecycline , revelation from Phase III study Treatment of patients with VAP need to increase the dose,1. Freire AT et al. D Microbiolo Infect Dis. 2010; 68(2):140 2.Brink AJ et al. SAMJ,2010,100(6):388 3.Crandon JL et al.Antimicrob Agents Chemother. 2009;53:5060,Tigecycline has faster clearance rate in VAP. Apparently decrease of AUC resulted to the decline of AUC/MIC, which made us unable to get the ideal therapeutic effect.,In the present study, pseudomonas occupied 39.6% in the group of Tigecycline treatment. Compared with the groups of Cephalosporin and Imipenem, it demonstrated that the therapeutic effects of Imipenem to pseudomonas were better than Cephalosporin treatment.,Tigecycline is a time-dependent and PAE anti- microbiologic agent with the characteristics of linear pharmacokinetics. Increasing the dose of Tigecycline is capable to elevate the beneficial effects of VAP.,Etiology,Further study,Tigecycline shows linear pharmacokinetic properties,Pharmacokinetic studies show that in a single dose of 12.5 -300 mg range, the Cmax, AUC of Tigecycline are proportional to the dosage.,Muralidharan G, et al. Antimicrob Agents Chemother. 2005;49(1):220-229.,Dose increasing study of Tigecycline: Study Design,Phase II, international multi-centers, double-blind, randomized, controlled, non-inferiority clinical trial screening total 114 patients with HAP or VAP in 75 research centers (Europe, Asia, Latin America, USAS, Canada and Australia): 108 cases into random (ITT population), 105 patients received treatment (safety , Mitt population) At the end of the study, 65 patients taking microbiological evaluation, 67 patients taking clinical evaluation,1:1:1 Randomized,TOC follow up,Tigecycline first dose 150 mg followed by 75 mg q12h i.v.,Imipenem / cilastatin 1 g q8h i.v.,If pseudomonas aeruginosa or MRSA infection can not be excluded : Two groups of tigecycline treatment received adjuvant therapy: ceftazidime 2 g q8h + aminoglycoside (tobramycin 7 mg / kg qd or amikacin 20mg/kg qd) + vancomycin placebo Group of imipenem / cilastatin treatment received adjuvant therapy: vancomycin 15 mg / kg + aminoglycoside (the tobramycin 7mg/kg qd or amikacin 20mg/kg qd) + ceftazidime placebo,Ramirez J, et al. Antimicrob Agents Chemother. 2013;57(4):1756-1762.,Tigecycline first dose 200 mg followed by 100 mg q12h i.v.,Therapeutical course 14 days,EOTafter10-21day,EOT: End of the treatment；TOC：Cure the check,Dose increasing stu