Chapter 34
Antimicrobial Chemotherapy
(항미생물화학치료)
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Chemotherapeutic Agents
• Chemical agents used to treat disease• Destroy pathogenic microbes or inhibit their growth within host
• Antibiotics (항생제)– Microbial products or their derivatives that kill susceptible microbes or inhibit their growth
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General Characterisitics of Antimicrobial Drugs
• Selective toxicity (선택적독성)– Ability of drug to kill or inhibit pathogen while damaging host as little as possible
• Therapeutic dose (치료량)– Drug level required for clinical treatment
• Toxic dose (독성량)– Drug level at which drug becomes too toxic for patient or produces side effects
• Therapeutic index (치료지수)– Ratio of toxic dose to therapeutic dose– The bigger, the better
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General Characteristics of Antimicrobial Drugs
• Side effects (부작용) – Undesirable effects of drugs on host cells
• Narrow‐spectrum drugs (협역약제) – Attack only a few different pathogens
• Broad‐spectrum drugs (광역약제) – Attack many different pathogens
• Cidal agent (살균) ‐ kills microbes
• Static agent (정균) ‐ inhibits growth of microbes4
General Characteristics of Antimicrobial Drugs
• Minimal inhibitory concentration (MIC, 최소억제농도)– Lowest concentration of drug that inhibits growth of pathogen
• Minimal lethal concentration (MLC, 최소치사농도)– Lowest concentration of drug that kills pathogen
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Determining the Level of Antimicrobial Activity
• Dilution susceptibility tests (희석감수성검사) – Broth or agar with lowest concentration showing no growth
• Disk diffusion tests (원판확산법)– Drug diffuses from disk into agar, establishing concentration gradient
• E‐test®6
항생제의 분류• Inhibitors of cell wall synthesis (세포벽생합성억제제)
• Protein synthesis inhibitors (단백질생합성억제제)
• Metabolic antagonists (대사길항제)• Nucleic acid synthesis inhibitors (핵산생합성억제제)
• Therapeutic index : I > P=M > N7
Inhibitors of Cell Wall Synthesis
• Penicillins– 6‐aminopenicillanic acid derivatives – Differ in side chain attached to amino group– ‐lactam ring
• Essential for bioactivity• Many penicillin‐resistant organisms produce ‐lactamase (penicillinase) which hydrolyzes a bond in this ring
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Mode of action of Penicillins 1
• D‐alanyl‐D‐alanine analog• Binds to penicillin‐binding protein (PBP)• Blocks the enzyme (transpeptidase, PBP) that catalyzes transpeptidation (formation of cross‐links in peptidoglycan)
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Mode of action of Penicillins 2
• Prevents the synthesis of complete cell walls leading to lysis of cell
• Stimulate release of autolysin which digests existing cell wall
• Acts only on growing bacteria that are synthesizing new peptidoglycan
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Mechanism of resistance to penicillin
• Transformation and homologous recombination ‐> altered penicillin binding protein
• Conjugation and plasmid transfer ‐> beta‐lactamase
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Naturally occurring penicillins
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• Narrow spectrum• Penicillin G and V • Active against gram (+)• Inactive against gram (‐)• Pen G
– Destroyed by gastric acid– Parental administration (주사제)
• Pen V– Resistant to gastric acid– Oral administration (경구투여)
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Naturally occurring penicillins
Semi‐synthetic penicillins • 6‐amino penicillanic acid (6‐APA) • Broader spectrum • Active against gram(+) and gram(‐)• Ampicillin, carbenicillin, and ticarcillin
• Penicillins resistant to penicillinase• Active against penicillin‐resistant bacteria• Methicillin, nafcillin, and oxacillin
• ~1–5% of adults in U.S. are allergic to penicillin14
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Semi‐synthetic penicillins
Cephalosporins
• 7‐aminocephalosporanic acid (7‐ACA)• Structurally and functionally similar to penicillins• Broad‐spectrum antibiotics that can be used by most patients that are allergic to penicillin
• Grouped into four categories based on their spectrum of activity (from narrow to broad)
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세대별세팔로스포린구분
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• 1세대 ‐그람양성균 > 그람음성균cephalothin
• 2세대 –혐기성세균을포함한그람음성균cefoxitin
• 3세대 –대부분의그람음성균, BBB(blood‐brain barrier)를통과, CNS에도달
cefoperazone• 4세대 – 가장광범위항생제
ceftriaxone
Vancomycin and Teicoplanin
• Glycopeptide antibiotics• Interact with D‐alanyl‐D‐alanine analog• Inhibit cell wall synthesis• Important for treatment of antibiotic‐resistant staphylococcal and enterococcal infections
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Vancomycin and Teicoplanin
• Drug of last resort
• Rise in resistance to vancomycin is of great concern
• VRSA (vancomycin‐resistant staphylococcus aureus) –반코마이신내성황색포도상구균
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Protein Synthesis Inhibitors• Many antibiotics bind specifically to the bacterial ribosome
• Binding can be to 30S (small) or 50S (large) ribosomal subunit
• Eukaryotic ribosome includes 40S and 60S• Other antibiotics inhibit a step in protein synthesis– Aminoacyl‐tRNA binding– Peptide bond formation– mRNA reading– Translocation
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Aminoglycosideantibiotics
• Large family which all contain a cyclohexane ring and amino sugars
• Bind to 30S ribosomal subunit • Interfere with protein synthesis by directly inhibiting the process and by causing misreading of the messenger RNA
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Aminoglycosideantibiotics
• Bacteriocidal• Resistance and toxicity (귀머거리, 신장손상, 균형감각상실, 구역질, 알레르기)
• Streptomycin, kanamycin, neomycin, tobramycin and gentamicin
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Tetracyclines
• All have a four‐ring structure to which a variety of side chains are attached
• Broad spectrum• Combine with 30S ribosomal subunit• Inhibit the binding of aminoacyl‐tRNA to the A site
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Tetracyclines
• Inhibits bind of aminoacyl‐tRNA molecules to the A site of the ribosome
• Bacteriostatic• Oxytetracycline, chlortetracycline, doxycycline
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Macrolides
• Contain 12‐ to 22‐carbon lactone rings linked to one or more sugars
• Erythromycin, clindamycin, and azithromycin• Broad spectrum, usually bacteriostatic• Binds to 23S rRNA of 50S ribosomal subunit• Inhibits peptide chain elongation • Used for patients allergic to penicillin
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erythromycin