Part 1. General considerations of antimicrobial agents ( ) Contents 1. Overview 2. Term and definition 3. Classification and mechanism of antibacterial action 4. Bacterial resistance History of Antimicrobial Therapy 1909 Ehrlich discovers Salvarsan Magic bullet for treatment of syphilis 1928 Fleming discovers penicillin 1932 Domagk discovers sulfonamides 1940s Penicillin and streptomycin used widely, cephalosporins discovered 1947 Chloramphenicol discovered 1950s Tetracycline in use 1952 Erythromycin discovered (macrolides ) 1956 Vancomycin used for penicillin-resistant S. aureus 1957 Kanamycin discovered (aminoglycosides ) 1962 Nalidixic acid discovered (quinolones ) 1980s Fluoroquinolones , broad spectrum cephalosporins 2000s Newer agents to combat resistant pathogens According to bioactivity Anti G + antibiotic Anti G - antibiotic Broad-spectrum antibiotic Anti mycobacterium antibiotic Anti anaerobe antibiotic -lactamase inhibitor Antimicrobial drugs classification According to the chemical structure 1 -lactams: Penicillins; Cephalosporins; 2 Aminoglycosides; 3 Macrolides; Lincosamides ;Vancomycins 4 Tetracyclines; Chloramphenicol 5 Quinolones 6 Sulphonamides 7 Nitrofurans 8 Antimycobacterial agents 9 others: Oxazolidinones; Streptogramins Antimicrobial drugs: Antibacterial drugs( ); Antifungal drugs( ); Antiviral drugs( ). Pharmacokinetics Adverse effects pathogenicity Immunologicalresponses Therapeutic Effects Resistance The relationship of the host, microorganisms, antimicrobial drugs. Terminology 1. Antibacterial drugs( ) 2. Antibiotics( ) 3. Bacteriostatic drugs( ) 4. Bactericidal drugs( ) 5. Antibacterial spectrum( ) 6. Chemotherapetic index ( ,CI) 7. Minimum inhibitory concentration ( , MIC) 8. Minimum bactericidal concentration ( , MBC) 9. Concentration Dependent killing 10. Time-dependent killing 11. Post antibiotic effect ( ,PAE) 12. First expose effect ( ): 2. Terms and definition: (1)Antibacterial drugs( ): Substances that can kill bacteria and/or inhibit its growth. including: Antibiotics( ); Synthetic antimicrobial agents, such as sulfonamides ( ) and quinolones ( ), etc. (2)Antibiotics( ): 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: LD 50 /ED 50, or LD 5 /ED 95 (4)Antibacterial spectrum ( ); (5)Bacteriostatic drugs ( ); (6)Bactericidal drugs ( ); Terms and definition agents Antimicrobial Susceptibility Testing 7. Minimum inhibitory concentration (MIC) 8. Minimum bactericidal concentration (MBC): concentration (MBC): 99.9% decrease in growth over 24 hours 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 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 (PAE ) 11. Post antibiotic affect (PAE ) : Persistence of suppression of bacterial growth after limited exposure to an antimicrobial agent. e.g. aminoglycosides 12. First expose effect ( ): aminoglycosides Terms and definition Classification and mechanism of action Comparison of the structure and composition of G + / G - cell walls. Penicillins transpeptidase vancomycin -Lactam antibiotics Classification and mechanism of action (1)Inhibiting synthesis of bacterial cell walls: (2)Affecting permeability of membrane: Ionic-adsorbed(streptomycin); binding to ergosterol(amphotercin B); Inhibiting the synthesis of ergosterol (imidazoles); Surface-active agent, that interact strongly with phospholipids(polymixins). Classification and mechanism of action (3)Inhibiting protein synthesis: affecting the function of 30S Streptomycin, Tetracyclines( ) affecting the function of 50S Streptomycin, Macrolides ( ), lincomycins, chloramphenicol etc. Classification and mechanism of action Inhibiting protein synthesis (4)Affecting bacterial nucleic acid metabolism: quinolones, etc. Classification and mechanism of action Pteridine( ) + PABA( ) sulfonamides Blocked by sulfonamides Dihydropteroic acid( ) Dihydrofolic acid( ) Glutaminic acid Tetrahydrofolic acid( ) trimethoprim Blocked by trimethoprim NADPH NADP Dihydropteroate synthase Dihydrofolate reductasease (5)Blocking enzymes of folate metabolism: Classification and mechanism of action Bacterial Resistance 4. Bacterial resistance: (1)Category of resistance: Intrinsic resistance: Inherent features usually expressed by chromosomal genes Acquired resistance: Acquired resistance: emerge from previously sensitive bacterial populations emerge from previously sensitive bacterial populations Caused by mutations in chromosomal genes Caused by mutations in chromosomal genes Or by acquisition of plasmids or transposons Or by acquisition of plasmids or transposons Bacterial Resistance (2)Mechanism of bacterial resistance: Enzymatic inactivation and modification; Inhance active efflux system: Decreased permeability; Target alteration; IM OM Penicillin -lactam Penicillinase Inactive 1A. Enzymatic inactivation e.g. -lactamase To produce inactivated enzyme: Kanamycin Acetylation Phosphorylation Adenylyation 1B. Enzymatic modification e.g. Aminoglycoside modification Bacterial Resistance Mechanism of bacterial resistance To enhance active efflux system ( ): Bacterial Resistance Mechanism of bacterial resistance Decreased permeability : Absence of, mutation in, or loss of the appropriate porins( ) channel can slow the rate of drug entry into the cell, or prevent entry altogether, reducing the effective drug concentration at the target site. Bacterial Resistance Mechanism of bacterial resistance Porin channel( ) Bact e rial Resistance Mechanism of bacterial resistance 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 Mechanism of bacterial resistance The transfer of resistance genes: Bacterial Resistance Mutations( ); Transduction( ); Transformation( ); Conjugation( ). Bacterial Resistance The transfer of resistance genes Mutations( ): 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( ) affecting expression of the target, a transport protein, or an inactivating enzyme. such as aminoglycosides, quinolones, etc. Bacterial Resistance Transduction( ): acquisition of bacterial DNA from bacteriophage( ) 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. Bacterial Resistance Transduction Transduction Bacterial Resistance Transformation( ): Uptake and incorporation of DNA that is free in the environment into the host genome by homologous recombination. Bacterial Resistance Conjugation( ): The passage of genes from cell to cell by direct contact through a sex pilus( ) or bridge( ).