General considerations of antimicrobial agents (抗微生物药物概论) Part 1. General considerations of antimicrobial agents (抗微生物药物概论)

Contents 1. Overview 2. Term and definition 3. Classification and mechanism of antibacterial action 4. Bacterial resistance

抗微生物药 Antimicrobial drugs: Antibacterial drugs(抗菌药); Antifungal drugs(抗真菌药); Antiviral drugs(抗病毒药).

The relationship of the host, microorganisms, antimicrobial drugs. Adverse effects Resistance Therapeutic Effects Pharmacokinetics pathogenicity Interactions between drug , human body, and pathogens is complex. Immunological responses

Terminology 1. Antibacterial drugs(抗菌药) 2. Antibiotics(抗生素) 3. Bacteriostatic drugs(抑菌药) 4. Bactericidal drugs(杀菌药) 5. Antibacterial spectrum(抗菌谱) 6. Chemotherapetic index (化疗指数,CI) 7. Minimum inhibitory concentration (最小抑菌浓度, MIC) 8. Minimum bactericidal concentration (最小杀菌浓度, MBC) 9. Concentration Dependent killing 10. Time-dependent killing 11. Post antibiotic effect (抗生素后效应,PAE) 12. First expose effect (首次接触效应): There are many terms to describe the antimicrobes properties.

2. Terms and definition: (1)Antibacterial drugs(抗菌药): Substances that can kill bacteria and/or inhibit its growth. including: ①Antibiotics(抗生素); ②Synthetic antimicrobial agents, such as sulfonamides (磺胺类) and quinolones (喹诺酮类), etc.

Terms and definition (2)Antibiotics(抗生素): Substances produced by various species of microorganisms (bacteria, fungi, actinomyces, etc.), which can kill other microorganisms or inhibit their growth.

Terms and definition (3)Chemotherapetic index (化疗指数) : LD50/ED50, or LD5/ED95 (4)Antibacterial spectrum(抗菌谱); (5)Bacteriostatic drugs(抑菌药); (6)Bactericidal drugs(杀菌药);

Terms and definition agents

Antimicrobial Susceptibility Testing 7. Minimum inhibitory concentration (MIC) 8. Minimum bactericidal concentration (MBC): 99.9% decrease in growth over 24 hours 7.Minimum inhibitory concentration (MIC) The lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism after overnight incubation Used by diagnostic laboratories mainly to confirm resistance, but most often as a research tool to determine the in vitro activity of new antimicrobials, and data from such studies have been used to determine MIC breakpoints. 8. Minimum bactericidal concentration (MBC) The lowest concentration of antimicrobial that will prevent the growth of an organism after subculture on to antibiotic-free media. MBC determinations are undertaken less frequently and their major use has been reserved for isolates from the blood of patients with endocarditis

Terms and definition 9. Concentration Dependent killing: situation in which the bactericidal activity of a drug depends by how much the drug concentration exceeds the Minimum inhibitory concentration. e.g. aminoglycosides and quinolones（有长PAE，首次接触效应） 10. Time-dependent killing: situation in which the bactericidal activity of a drug depends how long the drug concentration exceeds the Minimum inhibitory concentration of the organism in question. e.g. -lactams and vancomycin （无首次接触效应） 11. Post antibiotic affect (PAE 抗生素后效应) : Persistence of suppression of bacterial growth after limited exposure to an antimicrobial agent. e.g. aminoglycosides，quinolones 12. First expose effect (首次接触效应): aminoglycosides 11. Post antibiotic effect (PAE) Refers to a period of time after complete removal of an antibiotic during which there is no growth of the target organism Several factors influence the presence or duration of the PAE including the type of organism, type of antimicrobial, concentration of antimicrobial, duration of antimicrobial exposure, and antimicrobial combinations.

Classification and mechanism of action ① ④ ⑤ ③ ②

Comparison of the structure and composition of G+/ G- cell walls. Penicillins Comparison of the structure and composition of G+/ G- cell walls.

Classification and mechanism of action (1)Inhibiting synthesis of bacterial cell walls: -Lactam antibiotics vancomycin transpeptidase

Classification and mechanism of action (2)Affecting permeability of membrane: ①Ionic-adsorbed(streptomycin); ②binding to ergosterol(amphotercin B); ③Inhibiting the synthesis of ergosterol (imidazoles); ④Surface-active agent, that interact strongly with phospholipids(polymixins).

Classification and mechanism of action (3)Inhibiting protein synthesis: affecting the function of 30S：Streptomycin, Tetracyclines(四环素类) affecting the function of 50S： Macrolides (大环内酯类), lincomycins, chloramphenicol etc.

Inhibiting protein synthesis 氨基苷类 氨基苷类 四环素类 氯霉素类 大环内酯类 林可霉素类

Classification and mechanism of action (4)Affecting bacterial nucleic acid metabolism: quinolones, etc.

Pteridine(蝶啶) + PABA(对氨苯甲酸) Blocked by sulfonamides Classification and mechanism of action (5)Blocking enzymes of folate metabolism: Pteridine(蝶啶) + PABA(对氨苯甲酸) Dihydropteroate synthase Blocked by sulfonamides Dihydropteroic acid(二氢蝶酸) Glutaminic acid Dihydrofolic acid(二氢叶酸) NADPH Dihydrofolate reductasease Blocked by trimethoprim NADP Tetrahydrofolic acid(四氢叶酸)

Bacterial Resistance

4. Bacterial resistance: (1)Category of resistance: ①Intrinsic resistance: Inherent features usually expressed by chromosomal genes ②Acquired resistance: emerge from previously sensitive bacterial populations Caused by mutations in chromosomal genes Or by acquisition of plasmids or transposons

(2)Mechanism of bacterial resistance: ①Enzymatic inactivation and modification; ②Inhance active efflux system: ③Decreased permeability; ④Target alteration;

Mechanism of bacterial resistance ①To produce inactivated enzyme: IM OM Penicillin b-lactam Penicillinase Inactive Kanamycin Acetylation Phosphorylation Adenylyation 1B. Enzymatic modification e.g. Aminoglycoside modification 1A. Enzymatic inactivation e.g. β-lactamase

Mechanism of bacterial resistance ② To enhance active efflux system(主动外排系统):

Mechanism of bacterial resistance ③ Decreased permeability : Absence of, mutation in, or loss of the appropriate porins(膜孔蛋白) channel can slow the rate of drug entry into the cell, or prevent entry altogether, reducing the effective drug concentration at the target site.

Porin channel(膜孔蛋白通道) Bacterial Resistance Mechanism of bacterial resistance Porin channel(膜孔蛋白通道)

Mechanism of bacterial resistance ④ Target alteration : Mutation of the natural target(such as resistance to fluoroquinolone). Target modification(ribosomal protection type of resistance to macrolides). Substitution with a resistant alternative to the natural, susceptible target (such as methicillin resistance in staphylococci).

Bacterial Resistance The transfer of resistance genes: ①Mutations(突变); ②Transduction(转导); ③Transformation(转化); ④Conjugation(接合).

The transfer of resistance genes Bacterial Resistance The transfer of resistance genes ①Mutations(突变): which may occur in the gene encoding. 1)The target protein; 2)The protein involved in drug transport; 3)Act on regulatory gene or promoter(启动子) affecting expression of the target, a transport protein, or an inactivating enzyme. such as aminoglycosides, quinolones, etc.

Bacterial Resistance

Bacterial Resistance ②Transduction(转导): acquisition of bacterial DNA from bacteriophage(噬菌体) that has incorporated DNA from a previous host bacterium within its outer protein coat. Some phages can carry plasmids that code for penicillinase, or genes encod-ing resistance to erythromycin, tetracy-cline, or chloramphenicol.

Transduction Bacterial Resistance Transduction is acquisition of bacterial DNA from a bacteriophage (噬菌体）that has incorporated DNA from a previous host bacterium within its outer protein coat. Some phages can carry plasmids that code for penicillinase, or genes encoding resistance to erythromycin, tetracycline, or chloramphenicol.

③Transformation(转化): Bacterial Resistance ③Transformation(转化): Uptake and incorporation of DNA that is free in the environment into the host genome by homologous recombination.

Bacterial Resistance ④Conjugation(接合): The passage of genes from cell to cell by direct contact through a sex pilus(性菌毛) or bridge(桥接).

控制细菌耐药措施 合理应用药物（可用一种不用多种，可用窄谱不用广谱，掌握预防、局部使用适应症） 耐药患者消毒隔离，防止院内交叉感染 加强管理（处方药）

History of Antimicrobial Therapy 1909 Ehrlich discovers Salvarsan（撒尔佛散，治疗梅毒特效剂） “Magic bullet” for treatment of syphilis（梅毒） 1928 Fleming discovers penicillin （青霉素） 1932 Domagk discovers sulfonamides（磺胺类药物） 1940s Penicillin and streptomycin （链霉素）used widely, cephalosporins （头孢菌素）discovered 1947 Chloramphenicol （氯霉素）discovered 1950s Tetracycline （四环素）in use 1952 Erythromycin （红霉素）discovered (macrolides大环内酯类) 1956 Vancomycin （万古霉素）used for penicillin-resistant S. aureus 1957 Kanamycin（卡那霉素） discovered (aminoglycosides氨基糖苷类) 1962 Nalidixic acid （萘啶酸）discovered (quinolones喹诺酮类) 1980s Fluoroquinolones（氟喹诺酮类）, broad spectrum cephalosporins 2000s Newer agents to combat resistant pathogens There is a very long history that people discovered many drugs to fight against microbes that cause diseases, but we haven’t got the final victory. Since, both microbes and cancer cells can evolve resistance to drug therapies.

Antimicrobial drugs classification According to bioactivity Anti G+ antibiotic Anti G- antibiotic Broad-spectrum antibiotic Anti mycobacterium（分支杆菌） antibiotic Anti anaerobe（厌氧菌） antibiotic β-lactamase inhibitor

According to the chemical structure： 1、β-lactams: Penicillins; Cephalosporins; 2、Aminoglycosides (氨基糖苷类); 3、Macrolides (大环内酯类); Lincosamides ;Vancomycins 4、Tetracyclines (四环素类); Chloramphenicol 5、Quinolones (喹诺酮类) 6、Sulphonamides (磺胺类) 7、Nitrofurans (硝基呋喃类) 8、Antimycobacterial agents 9、others: Oxazolidinones; Streptogramins