Beta Lactams
β-lactam治疗G-菌感染的几点思考
孢菌素、氟喹诺酮类
• 侵袭性泌尿道操作
解放军昆明总医院药学部
Beta-lactam
非发酵菌R/S
铜绿假单胞菌
头孢哌酮-舒… 替卡西林-克… 哌拉西林-他… 美罗培南 亚胺培南 氨曲南 头孢吡肟 头孢哌酮 头孢他啶 哌拉西林
0 19.6 24.6 10 20 30 40 50 18.3 34.5 17.5 27.1 29.1 29.4 49.9 71.7 49.6 74 62.6 60 70 80 90 100 19.8 38.3 62.5 19.7 68.4 67.7 66.6
解放军昆明总医院药学部
Beta-lactam
临床分离到非发酵菌，首先要区分定植还是感染，特别是呼吸道标本！
铜绿假单胞菌
皮肤粘膜屏障发生破坏，如气管插管、机械通气、严重烧伤、留 置胃管
免疫功能低下，如中性粒细胞缺乏、实体肿瘤化疗、糖皮质激素
治疗、AIDS、菌群失调 慢性结构性肺病，如支气管扩张、COPD、肺囊性纤维化
19.6
5.1
20
思考2：检出率如此乊高，耐药严重，我们该怎么办？
• 相对于肠杆菌科，非发酵菌更强调患者的评估
解放军昆明总医院药学部
Beta-lactam
体表定植的正常微生物群
表皮葡萄球菌 座疮丙酸杆菌 棒状杆菌属 康状鳞斑霉 金黄色葡萄球菌 链球菌属 消化球菌属 分支杆菌属 芽孢杆菌属 丌动杆菌 肠杆菌科 假单胞菌 念珠菌
参考患者的临床表现
如果患者没有感染的临床症状，PA培养阳性多考虑定植，可以观察
如果患者有相应的感染征象，如发热，咯脓性痰，痰液粘稠，应考虑
感染的可能，再结合痰涂片镜梱和培养结果，迚行综合分析。
解放军昆明总医院药学部
β-内酰胺抑制剂
Beta-Lactamase InhibitorsSharon S.Castle VA Medical Center,Huntington,United Statesã2007Elsevier Inc.All rights reserved.IntroductionBeta-lactamase inhibitors enhance the activity of beta-lactam antibacterials against beta-lactamase-producing bacteria.These agents cause irreversible inhibition of many plasmid-mediated and some chromosomal beta-lactamases.They result in successful inhibition of beta-lactamases produced by gram-positive bacteria including Staphylococcus aureus,and gram-negative bacteria including H.influenzae,Neisseria gonorrhoeae,Moraxella catarrhalis,Bacteroides fragilis,and some Enterobacteriaceae.Because the beta-lactamase inhibitors are generally less effective against chromosomally mediated type1beta-lactamases,many Citrobacter,Enterobacter,Morganella,and Serratia spp.,and Pseudo-monas aeruginosa are resistant to them.Clavulanic acid,sulbactam,and tazobactamare beta-lactamase inhibitors.Whereas clavulanic acid is used in combination with amoxicillin and ticarcillin,sulbactam sodium is used in combination with ampicillin and cefoperazone,and tazobactam in combination with piperacillin Wright(1999),Sweetman (2003).Human PharmacokineticsClavulanic acid,sulbactam,and tazobactam are widely distributed throughout the body.They have a half-life of approximately1hour and are excreted by the kidneys.Targets-PharmacodynamicsBeta-lactamase inhibitors bind irreversibly to the catalytic site of beta-lactamase,pre-venting hydrolysis of the beta-lactam antibiotic.Beta-lactamase inhibitors also binddirectly to bacterial penicillin binding proteins,enhancing the antibacterial activity ofthe beta-lactam antibiotics.Clavulanic acid,which is administered as the potassium salt,has a chemical structure resembling the penicillin nucleus,except that the fused thiazo-lidine ring is replaced by an oxazolidine ring.In general,clavulanic acid has only weak antibacterial activity.Sulbactam and tazobactam are penicillanic acid sulfonic derivativeswith similar chemical structures.Clavulanic acid and tazobactam are more potent inhi-bitors of beta-lactamases.While clavulanic acid induces chromosomal beta-lactamse production,tazobactam and sulbactam do not Wright(1999),Sweetman(2003).Target Name(s):Beta-lactamase1TherapeuticsBeta-lactamase inhibitors bind irreversibly to the catalytic site of beta-lactamase,preventing hydrolysis of the beta-lactam antibiotic.They also bind to bacterial penicillin binding proteins,increasing the antibacterial activity of the antibiotics.Clavulanic acid has a chemical structure resembling the penicillin nucleus,except that the fused thiazo-lidine ring is replaced by an oxazolidine ring.In general,clavulanic acid displays only weak antibacterial activity.Sulbactam and tazobactam are penicillanic acid sulfonic derivatives with similar chemical structures.Clavulanic acid and tazobactam are more potent inhibitors of beta-lactamases.These agents inhibit beta-lactamases produced by gram-positive bacteria such as Staphylococcus aureus ,and gram-negative bacteria includ-ing H.influenzae ,Neisseria gonorrhoeae ,Moraxella catarrhalis ,Bacteroides fragilis ,and some Enterobacteriaceae.Because they are generally less effective against chromosomally mediated type 1beta-lactamases,many Citrobacter,Enterobacter,Morganella,Serratia spp.,and Pseudomonas aeruginosa remain resistant.While clavulanic acid induces chromo-somal beta-lactamase production,tazobactam and sulbactam do not Wright (1999),Sweetman (2003).IndicationsValue Units Prep.and Route of Admin.Reference Comments Infections caused by organisms producing beta-lactamases.The beta-lactamase is always used in combination with a beta-lactam antimicrobial,such as penicillin.ContraindicationsThese agents are contraindicated in those known to be hypersensitive to them or to lactam antibiotics.Adverse EffectsSide effects are normally related to the beta-lactam antibiotic rather than to the beta-lactamase itself.Included are nausea and vomiting,which appear to be related to the dose of clavulanic acid when it is used in combination with amoxicillin.Certain preparations of amoxicillin/clavulanic acid contain aspartame,which is metabolized to phenylalanine,which can be harmful in some individuals American Hospital Formulary System (2001).Pre-Clinical ResearchClavulanate potassium is extensively metabolized.In rats and dogs,the major metabolite is 1-amino-4-hydroxybutan-2-one,which has also been found in human urine following of this agent.Approximately 34%of an administered dose is excreted in the urine American Hospital Formulary System (2001).Journal CitationsWright,A.J.,1999.The penicillins.Mayo Clinic Proceedings ,74,300–301.Beta-Lactamase Inhibitors2Beta-Lactamase Inhibitors3 Book CitationsSweetman,S.,Expires12/2003.Martindale:The Complete Drug Reference.Sweetman,S.(Ed.)Micromedex,Electronic Version.Pharmaceutical Press,Greenwood Village,Colorado.American Hospital Formulary System2001Drug Monographs.McEvoy,G.(Ed.).American HospitalFormulary System,pp.383–389,American Society of Health-System Pharmacists,Inc.,Bethesda,Maryland.。
改进药敏折点标准
Change in Log CFU/Thigh or Lung Over 24 or 48 Hrs
2
Pneumonia - 48 Hrs
Thigh - 24 Hrs
0
-2
-4
0
20
40
60
80
100
050411
Time Above MIC (% of Dosing Interval)
29
Craig CID 33(Suppl 3):S233, 2001
• 不治疗对照 80-
100
100% 死亡
• 药代学提供了数
80
据可计算PK/PD
60
参数量
• 最后一次剂量的
40
第24小时计算死
亡率
20
• 数据来自3种动物、 0 4个感染部位
050411
Streptococcus pneumoniae
Cephalosporins Penicillins
0 20 40 60 80 100
050411
JAC 2003
17
P1010057-88
• ESBL相关的耐药机制对头孢菌素的破坏程度是不一的（2）； ESBL还常常与其它耐药机制共处；酶在不同细菌之中表达水平 也不同（2）因此，有可能某些头孢菌素对临床存在的某些ESBL 是有效的。
• 不幸，文献中缺乏足够数据，细菌水解各种头孢菌素的能力标记 不明确，严重的限制了对不同细菌的治疗选择。
050411
32
头孢匹肟对大肠杆菌及肺炎克雷伯菌的PKPD的靶值
当3种匹肟剂量为每12小时1克时或2克、或每8小时1克，PKPD靶值在MIC为 4ug/ml点上均可达>90%概率
重症脓毒血症和脓毒血性休克的抗生素治疗
大环内酯类 氮杂内酯类 克林霉素 四环素类 糖肽类 噁唑烷酮类
PK/PD参数：与 AUC/MIC比值相关
精C选rpapitg, 4th ISAAR, Seoul 2003
9
抗生素的分类及药效动力学（PD）指标
Crit Care Med 2009; 37(3): 840-51
140 ml/min/1.73 m2
140 ml/min/1.73 m2
精选ppt
27
61例延长滴注美平和哌拉西林/他唑巴坦的病人，28/61(48%)的病人没有达到 PK/PD的目标值 (100 % fT>MIC),28例中80%的病人测定的肌酐清除率 > 130 mL/min.多元回归分析证实高的肌酐清除率是不能够达到PK/PD目标值的独立预计 值。7/19病人(37 %)显示肌酐清除率> 130 ml/min 不能达到PK/PD目标值的 50 %
精选ppt
20
20
对抗生素PK/PD的影响因素
一、抗生素的分布容积改变：Vd增加，重要靶器官和末梢靶组 织出现抗生素的亚治疗浓度：
1、液体溢出：水肿、脓毒症、创伤、低白蛋白血症、输入液 体过量、肾和心功能衰竭
2、液体丧失：外科引流和烧伤 3、局部液体过量：胸腔积液和腹水 4、低白蛋白血症：40-50%的重症患者血白蛋白低于25g/L。
Marta Ulldemolins et al. CHEST 2011; 139: 1210 – 1220
Tulien Textoris,et al.Eui J Anaes精th选epspitol 2011;28:318-324
21
SIRS 对抗生素分布容积的影响
青霉素的作用机制
谢 谢 ！
欢迎批评指正！
青霉素的作用机制
1929年英国 科学家弗莱明 发现青霉素。
抗菌机制
(1)与PBPS结合，抑制转肽
酶，阻碍了细胞壁合成；
(2)激活自溶酶活性。
β－内酰胺环
外膜
细 胞 壁
肽 聚 糖-乙酰葡糖胺） N-acetylglucosamine
UDP NAG
NAM（ N-乙酰胞壁酸） N-acetylmuramic acid
肺炎链球菌、金黄色葡萄球菌
G+杆菌 白喉棒状杆菌、炭疽芽孢杆菌 厌氧杆菌等 G－球菌 脑膜炎奈瑟菌、淋病奈瑟菌 螺旋体 苍白密螺旋体、钩端螺旋体 放线菌
临床应用
天然青霉素肌内注射或 静滴为治疗敏感菌感染的首
选药。
溶血性链 与抗毒 放线菌病 肺炎球 脑膜炎 草绿色链 球菌引起 素合用 菌所致 球菌引 球菌引起 钩体病 咽炎、 治 疗： 大叶性 起流行 的感染性 扁桃体炎 破伤风 梅 肺炎、 毒 性脑脊 心内膜炎 腥红热、 白 喉 中耳炎 髓膜炎 败血症等
细胞膨胀、变形 胞破裂溶解而死亡。
细
自溶酶的作用
葡萄球菌
给药后的葡萄球菌
+ G
－ G
抗菌特点
(1)繁殖期杀菌药；
(2)对G－作用弱、因为G－细胞壁 肽聚糖含量少且胞浆渗透压低；
(3)对人体毒性小；对真菌和病
毒感染无效。
抗菌作用与抗菌谱
杀菌药
天 然 青 霉 素
G+球菌
溶血性链球菌、草绿色链球菌
UDP NAM L-丙氨酸 D-谷氨酸
例如：金黄色葡萄球菌
L-赖氨酸 D-丙氨酸 D-丙氨酸
细胞壁的形成2
NAG
NAM
微生物耐药性论文 (9)
E-mail address: alishah_75@ (A.A. Shah). 0923-2508/$ – see front matter 2004 Elsevier SAS. All rights reserved. doi:10.1016/j.resmic.2004.02.009
Байду номын сангаас
Abstract β-Lactam antimicrobial agents represent the most common treatment for bacterial infections and continue to be the leading cause of resistance to β-lactam antibiotics among Gram-negative bacteria worldwide. The persistent exposure of bacterial strains to a multitude of β-lactams has induced dynamic and continuous production and mutation of β-lactamases in these bacteria, expanding their activity even against the newly developed β-lactam antibiotics. These enzymes are known as extended-spectrum β-lactamases (ESBLs). The majority of ESBLs are derived from the widespread broad-spectrum β-lactamases TEM-1 and SHV-1. There are also new families of ESBLs, including the CTX-M and OXA-type enzymes as well as novel unrelated β-lactamases. In recent years, there has been an increased incidence and prevalence of ESBLs. ESBLs are mainly found in strains of Escherichia coli and Klebsiella pneumoniae but have also been reported in other Enterobacteriaceae strains and Pseudomonas aeruginosa. Infections with ESBL-producing bacterial strains are encountered singly or in outbreaks, especially in critical care units in hospitals, resulting in increasing cost of treatment and prolonged hospital stays. Not only may nursing home patients be an important reservoir of ESBL-containing multiple antibiotic-resistant organisms, but ambulatory patients with chronic conditions may also harbor ESBL-producing organisms. 2004 Elsevier SAS. All rights reserved.
Beta-lactams_E
Antiinfective agents may be classified according to their antimicrobial activity: 1. Antibacterial drugs (antibiotics
and synthetic drugs) 2. Antiviral drugs 3. Antifungal drugs 4. Antiprotozoal drugs 5. Anthelmintic drugs 6. Insecticides for ectoparasites 7. Antiseptics and Disenfectant (Not are drugs) 8. Prepartaions for Disinsection (Not are drugs) 9. Prepartaions for Deratisation (Not are drugs) 10. Vaccines, Serums, and Immunoglobulins
ANTIBIOTICS – mechanism of action
β-lactams, Glycopeptides
30S: Aminoglycosides 30S: Tetracyclines 50S: Chloramphenicol 50S: Macrolides, Lincosamides 50S: Linezolide, Streptogramins
●reduced phagocytosis, and chemotactic activity of neutrophils (tetracyclines) ●inhibition of phagocytosis (aminoglycosides) ●hypersensitivity reactions (beta-lactams, aminosides, sulfonamides) ●hepatic microsomal enzyme induction (e.g. rifampin) or inhibition (e.g. chloramphenicol) that interferes with their own metabolism as well as that of concurrent medications,
抗生素耐药的机理(英文)
• Trigger membrane associated autolytic enzymes that destroy cell wall
• Inhibit bacterial endopeptidase and glycosidase enzymes which are involved in cell wall growth
Clin. Microbiol. Rev.10:781-791, J.Infect.Dis.162:705-710
Result
• All PBPs in S.aureus become redundant –MRSA is resistant to all ß-lactams
Mutation by Recombination with Foreign DNA
– Reduced affinity to beta lactams
• Seen as penicillin resistant Pneumococci
Beta Lactam Activity Against 100 Penicillin Resistant Pneumococci from Spain
CHз
HO
o
Carbapenems 1976-
SR N
COOH
HO
o
N
o
Clavulanic acid 1976 COOH
Mobactams
R
R-CONH
o
Monobactam 1981-
N
R
Mechanisms of Action
抗菌素种类及应用
β内酰胺类抗生素，氨基甙类抗生素，大环内酯类抗生素及喹诺酮类抗菌药为目前应用较广的几类抗感染药物。
目前在我国临床应用中的比例约为：β内酰胺类抗生素占50%左右；喹诺酮类抗菌药约占20%；氨基甙类抗生素约占8%；大环内酯类抗生素约占4%。
以上四类抗菌药占临床用量的80%以上，可见其临床地位之重要。
【β-内酰胺类抗生素（Beta-lactams）】1、青霉素类（Penicillins）窄谱青霉素：青霉素G(benzylpenicillin), 青霉素V(phenoxymethylpenicillin)和普鲁卡因青霉素(procaine penicillin)。
主要用于革兰氏阳性菌肺炎球菌感染。
我国耐青霉素G的肺炎球菌目前仅约不足10%，尚不构成太大的治疗难题，且中度敏感菌株可通过增加青霉素剂量解决，故仍可将其列为肺炎球菌感染的首选药物之一。
青霉素V对酸稳定，因此可口服给药。
需注意的是食物对其吸收有一定影响。
普鲁卡因青霉素，只能用于肌注。
因其半衰期长可每日一次给药。
目前已少用。
耐酶青霉素：有称为抗葡萄球菌青霉素者。
主要包括甲氧西林(methicillin)，氯唑西林(cloxacillin)，氟氯西林(flucloxacillin)，双氯西林(dicloxacillin)和苯唑西林(oxacillin)。
因其可耐受由葡萄球菌产生的β内酰胺酶而得名。
主要用于产β内酰胺酶葡萄球菌的治疗。
以上各药抗菌谱相似，但甲氧西林因毒性大已弃用。
氟氯西林和双氯西林口服吸收优于氯唑西林故而胃肠道反应少。
氟氯西林一般耐受较好，但发现在某些患者可导致胆汁阻塞性黄疸，尤多见于老年患者。
多在用药后6周出现，可持续数月。
双氯西林肝毒性较小，较适用于老年患者。
此类青霉素对肺炎球菌及其他革兰氏阳性球菌作用不及青霉素G，对革兰氏阴性杆菌及肠球菌无效。
故仅用于产β内酰胺酶的葡萄球菌。
临床上认为，不管实验室药敏结果如何，耐甲氧西林金葡菌（MRSA）对所有β内酰胺类抗生素均耐药。
Beta-Lactam Antibiotics - at SMU
1960’s to today- novel β-lactams/ β-lactamase inhibitors are discovered and modified from the natural products of baceptidase- PBP
β-lactams mimic the structure of the D-Ala-D-Ala link and bind to the active site of PBPs, disrupting the cross-linking process.
Mechanism of β-Lactam Drugs
Mechanism of β-Lactam Drugs
The PBP is now covalently bound by the drug and cannot perform the cross linking action.
Bacterial Resistance
Bacteria have many methods with which to combat the effects of β-lactam type drugs.
β-Lactams are divided into several classes based on their structure and function; and are often named by their origin, but all classes have a common β-Lactam ring structure.
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Penicillin-G
Ⅲ. Uses :
Streptococcal infections- pharyngitis, otitis media, scarlet fever, rheumatic fever Subacute bacterial endocarditis (SABE)- Streptococcus viridans or S. faecalis- penicillin + aminoglycoside (streptomycin/ gentamicin) synergistic Pneumococcal infections- high resistance, not used now Meningococcal infections- still responsive; rifampin for prophylaxis Staphylococcal infections- penicillinase resistant or antistaphylococcal penicillin preferred Gonorrhea- high resistance, ciprofloxacin/ ceftriaxone preferred
2
Tuesday, December 23, 2014
Overview
Inhibitors of cell wall synthesis : Beta Lactams Penicillins Cephalosporins Monobactams- aztreonam Carbapenems- imipenem Vancomycin Cycloserine Bacitracin
18 Tuesday, December 23, 2014
Penicillin-G
Ⅲ. Uses :
Syphilis- drug of choice Diphtheria- antitoxin (main) , penicillin as adjuvant Tetanus, gas gangrene- antitoxin (main), penicillin as adjuvant Actinomycosis, Nocardiosis, anthrax, trench mouth, rat bite fever, Listeria infections Prophylaxis- benzathine penicillin Rheumatic fever, gonorrhea or syphilis Agranulocytosis and surgical patients- with aminoglycoside
Ⅱ. Mechanism of action
Characteristics :
(1) Bactericidal (2) Most effective during rapid cell division (Reproductive period bactericidal) (3) Nontoxic to man
Preparations :
Sodium penicillin G (crystalline penicillin) injection Potassium penicillin for oral use- 1 hr before or 2 hrs after food Repository PnG injections- insoluble salts, given i.m Procaine penicillin- 12- 24 hourly, lower but sustained (1-2 days) levels attained Fortified procaine penicillin- rapid and sustained levels Benzathine penicillin- every 2-4 weeks, levels low but effective for prophylaxis for up to 4 weeks
Excreted by tubular secretion in kidney (slow: neonates,
elderly and those with renal failure ), blocked by probenecid- duration of action of penicillin prolonged.
3
Tuesday, December 23, 2014
Overview
Common feature of beta lactams :
Ⅰ. Chemistry
4
Tuesday, December 23, 2014
Overview
Common feature of beta lactams :
Ⅱ. Mechanism of action
B. Cell-wall autolytic enzyme
6 Tuesday, December 23, 2014
Overview
7
Tuesday, December 23, 2014
Overview
8
Tuesday, December 23, 2014
Overview
Common feature of beta lactams :
Inhibitors of Cell Wall Synthesis:
Beta lactams antibiotics
Dr. Lei Shen Dept. of Pharmacology
Aims and requirements
1. To master the mechanism of action and the bacterial resistance of β-lactam antibiotics. 2. To master the antibacterial spectrum, clinical use, adverse reactions and prophylactic measures of penicillinG. 3. To master the antibacterial spectrum, clinical use, adverse reactions of four generations of cephalosphorins. 4. Familiar with the characteristics and clinical uses of each category of semisynthesized penicillin. 5. To understand the characteristics of other β-lactam antibiotics.
10
Tuesday, December 23, 2014
Overview
Common feature of beta lactams :
Ⅲ. Bacterial resistance
Acquired:
(2) Change in porin (Pseudomonas) or PBP (MRSA, pneumococci) structure → resistance
13
Tuesday, December 23, 2014
Penicillin
14
014
Penicillin-G (PnG, Benzyl penicillin)
Unitage :
1 U of crystalline sod. benzyl penicillin = 0.6 pg of the standard preparation. Thus 1 g = 1.6 million units or 1 MU = 0.6 g.
5 Tuesday, December 23, 2014
Overview
Common feature of beta lactams :
Ⅱ. Mechanism of action
A. Inhibition of bacterial cell wall synthesis
(2) Penicillin resembles D-Ala – D-Ala, blocks cleavage of terminal D-Ala and transpeptidation. These enzymes and related proteins involved in peptidoglycan synthesis called as PBPs (penicillin binding proteins). (3) Due to osmosis, bacterium swells, giant forms → cell lysis
11
Tuesday, December 23, 2014
Overview
beta lactamase
Change in porin or PBP
12 Tuesday, December 23, 2014
Penicillin
Basic structure: 6 – APA (6 – aminopenicillanic acid) Classification Natural penicillins Semisynthesized penicillins
16
Tuesday, December 23, 2014
Penicillin-G
Ⅱ. Antibacterial spectrum :
Narrow spectrum; primarily to gram-positive bacteria.
Gram-positive cocci : Streptococci, pneumococci, staphylococci (acquired resistance) Gram-negative cocci : Meningococci, diplococci, gonorrhoeae Gram-positive bacilli : Bacillus anthracis, corynebacterium diphtheriae, clostridium (tetani and others) Spirochete : Treponema pallidum, Leptospira, and others