抗生素合理使用
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Susceptible bacteria
(MIC of mutants)
MIC
Concentration (µg/ml)
Cmax
MPC Window of selection
MIC
Tmax
Time post administration (h)
Baquero & Negri. BioEssays 1997; 19: 731-6 Drlica K. ASM News 2001; 67:27-33 Cantón et al. Inter J Antimicrob Chemother 2006 (in press)
100
MIC = 16 mcg/mL
10
Concentration (mcg/mL)
1
0.1
T>MIC exposure was 40% of the dosing interval at the MIC of 16 mcg/mL
0 8 16 24 32 40
Time (h)
Kuti JL et al. Pharmacotherapy. 2004;24:1641-1645
60 40
20 00 5
Data from 107 acutely ill patients with nosocomial RTIs treated with 5 different antibiotic regimens (ciprofloxacin, cefmenoxime, ceftazidime, ciprofloxacin plus piperacillin, ceftazidime plus tobramycin)
抗生素使用目标
控制感染
合理药物, 途径,方式
较少 副作用
正常菌群 稳定
合理剂量 疗程
Pharmacology of Antimicrobial Therapy
Concentrations in tissues and body fluids Pharmacologic and toxicologic effect
-a combination of PK and PD
PK/PD Predictors of Efficacy
Cmax
Parameters of interest
•T > MIC
•Cmax, Cmax/MIC •24h-AUC/MIC (AUIC) 24h-AUC
T>MIC
MIC90
Dose
Time
Dose
依据PK/PD抗菌药物分类
浓度依赖性 时间依赖性 与时间有关,但抗菌活性持 续时间较长 时间依赖且 抗菌作用与 同细菌接触时间密切相关 PAE或T1/2较长
对致病菌的杀菌作用 取决于峰浓度
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β-内酰胺类、 林可霉素类 恶唑烷酮类、氟胞嘧啶
Meropenem 500 mg Administered as a 0.5 h or 3 h Infusion
100.0
Rapid Infusion (30 min) Extended Infusion (3 h)
10.0
Concentration (mcg/mL)
1.0
MIC
0.1 0 2 4 6 8
Drusano GL. Clin Infect Dis. 2003;36(suppl 1):S42-S50.
-内酰胺类-优化暴露时间
-Lactam: Optimizing Exposure
Maximizing T>MIC
提高剂量-安全性前提 增加给药频率 延长输注时间
Drusano. Clin Infect Dis 20பைடு நூலகம்3;36(Suppl. 1):S42–S50
Microbiological Clinical
0–62.5
62.5–125
125–250 AUC:MIC
250–500
>500
Forrest et al. Antimicrob Agents Chemother 1993;37:1073–1081
Gram-Negative Bacterial Eradication and Fluoroquinolone AUIC
Aminoglycoside:optimal Cmax:MIC
-Relationship Between Cmax:MIC and Clinical Response
Clinical response (%) 100 80
65 83 70
89
92
60 40 20
55
0
2
4
6 8 Cmax :MIC
10
12
Moore et al. J Infect Dis 1987;155:93–99
What is the Optimal AUIC for Fluoroquinolones?
30
125
For G+
For G-
Fluoroquinolone Therapy for Nosocomial Pneumonia
感染引起的SIRS
MODS的表现
Severe Sepsis 治疗
• • • • • • • 感染源的处置 抗菌药物使用 循环支持 机械通气 肾脏替代 镇静/止痛 营养
Wheeler AP, Bernard GR.Treating patients with severe sepsis. N Engl J Med. 1999 Jan 21;340(3):207-14. Review.
SIRS
Bone RC, Balk RA, Cerra FB, et al. Chest. 1992 Jun;101(6):1644-55. Review.
SEPSIS
Bone RC, Balk RA, Cerra FB, et al. Chest. 1992 Jun;101(6):1644-55. Review.
-Correlation Between Drug Exposure (AUC/MIC) & Outcome
Patients cured (%)
100 80 60 40 20 0
AUC:MIC>125
lead to appropriate clinical and microbiological outcome
常见的致死率高的临床综合症
严重感染-发展趋势
• • • • • 人口老龄化 医疗水平提高,生命支持治疗发展 免疫功能低下(肿瘤治疗、器官移植) 介入性技术和装置推广应用 细菌耐药性与院内感染增多
严重感染与其他疾病比较
发病率 死亡率
National Center of Health Statistics.2001. American Cancer society,2001
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 T>MIC和AUC>MIC
主要参数 T>MIC,PAE,T1/2 AUC/MIC
-lactam:optimal T>MIC?
Required %T>MIC for static
-20% for carbapenems -30% for penicillins -40% for cephalosporins
Required %T>MIC for cidal:
– ~ 40% for carbapenems – ~ 50% for penicillins – ~70% for ephalosporins
Time (h)
Dandekar PK et al. Pharmacotherapy. 2003;23:988-991.
Treatment of Multidrug-resistant Burkholderia cepacia With Prolonged Infusion Meropenem
Meropenem 2 g infused over 3 hours q 8 h
Dosing regimen
Concentrations in serum
MIC、 MBC Concentrations at site of infection Antimicrobial effect
Absorption Distribution Elimination
Pharmacokinetics (PK)
• Efficacy
– Cmax/MIC ratio 8-10 – 24-h AUC/MIC(AUIC)
Total AUIC >100
Free AUIC >30-40
• Resistance prevention
– Cmax >MPC – Higher AUIC
MPC
Resistant mutant
AUC0–24h:MIC <100
10 15 Days from initiation of therapy
20
Thomas KL et al. Antimicrob Agents Chemother. 1998;42:521–527
Optimizing FQs therapy for S. pneumoniae from PK/PD point of view
% Patients remaining culture positive 100
Higher AUC:MIC lead to letter bacterial eradication
AUIC < 125
75
50
25
AUIC 125-250
0
0 2 4 6 8 10 12 14
AUIC > 250
Days
Pharmacodynamics (PD)
抗菌药物起效过程
剂量 药动学
溶解 吸收 分布 代谢 排泄
药效学
时间依赖杀菌 浓度依赖杀菌 抗生素后效应
起效
细菌数量 死亡率 症状体征识别
药代动力学和MIC
Different pattern of time-killing of 3 Abx VS Pseudomonas
重症患者抗菌药物使用
重症患者,运用PK/PD理论合理的使 用抗菌药物,同时还要关注重症患者 的全身情况
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 -静脉
Forrest et al. Antimicrob Agents Chemother. 1993;37:1073-1081
Probability of Developing Resistance
Probability of remaining susceptible (%) 100 80
AUC0–24h:MIC 100
感染的相关概念
ACCP/SCCM联席会议定义
Bone RC, Balk RA, Cerra FB, et al. Chest. 1992 Jun;101(6):1644-55. Review.
Bone RC, Balk RA, Cerra FB, et al. Chest. 1992 Jun;101(6):1644-55. Review.
急诊抗生素合理使用
主要内容
• • • • • 流行病学 感染相关概念 PK/PD理论 细菌耐药与抗菌药物使用 急诊常见感染病处置
流行病学-严重感染
• 非心脏ICU患者的首要死亡原因 • 年死亡率与心肌梗塞相同 • 在美国人口的所有死因中居第11位 每年约750,000例严重感染 发病率:3/1000 每年死亡患者超过225,000例 死亡率:约30%
SEVERE SEPSIS
感染的演变过程
Infection /Trauma
SIRS
SEPSIS
SEVERE sepsis
MODS
具有两项一下临床表现: 1.体温>38 ℃或<36 ℃ 2.心率>90次/分 3.呼吸频率>20次/分 4.白细胞计数>12,000/mm3或 <4,000/mm3或幼粒细胞>10%
Killing and rate of killing depends on concentration
Rate of killing increases no more as concentration increases, killing depends on exposure time
PK/PD Predictors of Efficacy
(MIC of mutants)
MIC
Concentration (µg/ml)
Cmax
MPC Window of selection
MIC
Tmax
Time post administration (h)
Baquero & Negri. BioEssays 1997; 19: 731-6 Drlica K. ASM News 2001; 67:27-33 Cantón et al. Inter J Antimicrob Chemother 2006 (in press)
100
MIC = 16 mcg/mL
10
Concentration (mcg/mL)
1
0.1
T>MIC exposure was 40% of the dosing interval at the MIC of 16 mcg/mL
0 8 16 24 32 40
Time (h)
Kuti JL et al. Pharmacotherapy. 2004;24:1641-1645
60 40
20 00 5
Data from 107 acutely ill patients with nosocomial RTIs treated with 5 different antibiotic regimens (ciprofloxacin, cefmenoxime, ceftazidime, ciprofloxacin plus piperacillin, ceftazidime plus tobramycin)
抗生素使用目标
控制感染
合理药物, 途径,方式
较少 副作用
正常菌群 稳定
合理剂量 疗程
Pharmacology of Antimicrobial Therapy
Concentrations in tissues and body fluids Pharmacologic and toxicologic effect
-a combination of PK and PD
PK/PD Predictors of Efficacy
Cmax
Parameters of interest
•T > MIC
•Cmax, Cmax/MIC •24h-AUC/MIC (AUIC) 24h-AUC
T>MIC
MIC90
Dose
Time
Dose
依据PK/PD抗菌药物分类
浓度依赖性 时间依赖性 与时间有关,但抗菌活性持 续时间较长 时间依赖且 抗菌作用与 同细菌接触时间密切相关 PAE或T1/2较长
对致病菌的杀菌作用 取决于峰浓度
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β-内酰胺类、 林可霉素类 恶唑烷酮类、氟胞嘧啶
Meropenem 500 mg Administered as a 0.5 h or 3 h Infusion
100.0
Rapid Infusion (30 min) Extended Infusion (3 h)
10.0
Concentration (mcg/mL)
1.0
MIC
0.1 0 2 4 6 8
Drusano GL. Clin Infect Dis. 2003;36(suppl 1):S42-S50.
-内酰胺类-优化暴露时间
-Lactam: Optimizing Exposure
Maximizing T>MIC
提高剂量-安全性前提 增加给药频率 延长输注时间
Drusano. Clin Infect Dis 20பைடு நூலகம்3;36(Suppl. 1):S42–S50
Microbiological Clinical
0–62.5
62.5–125
125–250 AUC:MIC
250–500
>500
Forrest et al. Antimicrob Agents Chemother 1993;37:1073–1081
Gram-Negative Bacterial Eradication and Fluoroquinolone AUIC
Aminoglycoside:optimal Cmax:MIC
-Relationship Between Cmax:MIC and Clinical Response
Clinical response (%) 100 80
65 83 70
89
92
60 40 20
55
0
2
4
6 8 Cmax :MIC
10
12
Moore et al. J Infect Dis 1987;155:93–99
What is the Optimal AUIC for Fluoroquinolones?
30
125
For G+
For G-
Fluoroquinolone Therapy for Nosocomial Pneumonia
感染引起的SIRS
MODS的表现
Severe Sepsis 治疗
• • • • • • • 感染源的处置 抗菌药物使用 循环支持 机械通气 肾脏替代 镇静/止痛 营养
Wheeler AP, Bernard GR.Treating patients with severe sepsis. N Engl J Med. 1999 Jan 21;340(3):207-14. Review.
SIRS
Bone RC, Balk RA, Cerra FB, et al. Chest. 1992 Jun;101(6):1644-55. Review.
SEPSIS
Bone RC, Balk RA, Cerra FB, et al. Chest. 1992 Jun;101(6):1644-55. Review.
-Correlation Between Drug Exposure (AUC/MIC) & Outcome
Patients cured (%)
100 80 60 40 20 0
AUC:MIC>125
lead to appropriate clinical and microbiological outcome
常见的致死率高的临床综合症
严重感染-发展趋势
• • • • • 人口老龄化 医疗水平提高,生命支持治疗发展 免疫功能低下(肿瘤治疗、器官移植) 介入性技术和装置推广应用 细菌耐药性与院内感染增多
严重感染与其他疾病比较
发病率 死亡率
National Center of Health Statistics.2001. American Cancer society,2001
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 T>MIC和AUC>MIC
主要参数 T>MIC,PAE,T1/2 AUC/MIC
-lactam:optimal T>MIC?
Required %T>MIC for static
-20% for carbapenems -30% for penicillins -40% for cephalosporins
Required %T>MIC for cidal:
– ~ 40% for carbapenems – ~ 50% for penicillins – ~70% for ephalosporins
Time (h)
Dandekar PK et al. Pharmacotherapy. 2003;23:988-991.
Treatment of Multidrug-resistant Burkholderia cepacia With Prolonged Infusion Meropenem
Meropenem 2 g infused over 3 hours q 8 h
Dosing regimen
Concentrations in serum
MIC、 MBC Concentrations at site of infection Antimicrobial effect
Absorption Distribution Elimination
Pharmacokinetics (PK)
• Efficacy
– Cmax/MIC ratio 8-10 – 24-h AUC/MIC(AUIC)
Total AUIC >100
Free AUIC >30-40
• Resistance prevention
– Cmax >MPC – Higher AUIC
MPC
Resistant mutant
AUC0–24h:MIC <100
10 15 Days from initiation of therapy
20
Thomas KL et al. Antimicrob Agents Chemother. 1998;42:521–527
Optimizing FQs therapy for S. pneumoniae from PK/PD point of view
% Patients remaining culture positive 100
Higher AUC:MIC lead to letter bacterial eradication
AUIC < 125
75
50
25
AUIC 125-250
0
0 2 4 6 8 10 12 14
AUIC > 250
Days
Pharmacodynamics (PD)
抗菌药物起效过程
剂量 药动学
溶解 吸收 分布 代谢 排泄
药效学
时间依赖杀菌 浓度依赖杀菌 抗生素后效应
起效
细菌数量 死亡率 症状体征识别
药代动力学和MIC
Different pattern of time-killing of 3 Abx VS Pseudomonas
重症患者抗菌药物使用
重症患者,运用PK/PD理论合理的使 用抗菌药物,同时还要关注重症患者 的全身情况
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 -静脉
Forrest et al. Antimicrob Agents Chemother. 1993;37:1073-1081
Probability of Developing Resistance
Probability of remaining susceptible (%) 100 80
AUC0–24h:MIC 100
感染的相关概念
ACCP/SCCM联席会议定义
Bone RC, Balk RA, Cerra FB, et al. Chest. 1992 Jun;101(6):1644-55. Review.
Bone RC, Balk RA, Cerra FB, et al. Chest. 1992 Jun;101(6):1644-55. Review.
急诊抗生素合理使用
主要内容
• • • • • 流行病学 感染相关概念 PK/PD理论 细菌耐药与抗菌药物使用 急诊常见感染病处置
流行病学-严重感染
• 非心脏ICU患者的首要死亡原因 • 年死亡率与心肌梗塞相同 • 在美国人口的所有死因中居第11位 每年约750,000例严重感染 发病率:3/1000 每年死亡患者超过225,000例 死亡率:约30%
SEVERE SEPSIS
感染的演变过程
Infection /Trauma
SIRS
SEPSIS
SEVERE sepsis
MODS
具有两项一下临床表现: 1.体温>38 ℃或<36 ℃ 2.心率>90次/分 3.呼吸频率>20次/分 4.白细胞计数>12,000/mm3或 <4,000/mm3或幼粒细胞>10%
Killing and rate of killing depends on concentration
Rate of killing increases no more as concentration increases, killing depends on exposure time
PK/PD Predictors of Efficacy