Chapter 38 Introduction To Chemotherapeutic Drugs Chapter 38 Introduction To Chemotherapeutic Drugs

Brief History of Chemotherapeutic Drugs Brief History of Chemotherapeutic Drugs 1910 Ehrlich Arsphnamine( 砷凡纳明 ) chemotherapy 1910 Ehrlich Arsphnamine( 砷凡纳明 ) chemotherapyEhrlich 1929 Fleming 1929 Fleming Fleming Fleming 1940 Florey and Chain Penicilin 1940 Florey and Chain PenicilinFlorey 1935 Domagk Prontosil （百浪多息） 1935 Domagk Prontosil （百浪多息）Domagk 1960 ’ s β-Lactam antibiotics 1960 ’ s β-Lactam antibiotics 1970 ’ s Fluoroquinolones 1970 ’ s Fluoroquinolones 1980 ’ s New Macrolides 1980 ’ s New Macrolides

Paul Ehrlich

青霉素发明者、英国科学家 弗莱明在他的实验室内 澳大利亚病理学家霍华德. 弗罗里因进行 青霉素化学制剂的研究，而与弗莱明 1945 年诺贝尔生理学和医学奖

Domagk

Relationship between pathogen, chemotherapeutic drugs and patients host Antimicrobial agents mycrobacterium Side effect process resistance Antimicrobial action pathogenicity immunity

Several Terms related to Chemotherapy Antimicrobial drugs(Antibacterial drugs, antifungal drugs, antiviral drugs) Antimicrobial drugs(Antibacterial drugs, antifungal drugs, antiviral drugs) Chemotherapy Chemotherapy Antibacterial drugs Antibacterial drugs Antibiotics Antibiotics Antibacterial spectrum Antibacterial spectrum Antibacterial activity Antibacterial activity Minimal inhibitory concentration (MIC) Minimal inhibitory concentration (MIC) Minimal bactericidal concentration (MBC) Minimal bactericidal concentration (MBC) Bacteriostatic drugs Bacteriostatic drugs Bactericidal drugs Bactericidal drugs Chemotherapeutic index(CI) Chemotherapeutic index(CI) Post-antibiotic effect ( PAE ) Post-antibiotic effect ( PAE )

Mechanism of action of the Antibacterial Agents Inhibiting the biosynthesis of the cell wall Inhibiting the biosynthesis of the cell wall Inhibiting the biosynthesis of the cell wall Inhibiting the biosynthesis of the cell wall β-lactam β-lactam Increasing the permeability of the cytoplasmic membrane Increasing the permeability of the cytoplasmic membrane Aminoglycosides Aminoglycosides Imidazoles(miconazole, ketoconazole) Imidazoles(miconazole, ketoconazole) Polymixins Polymixins Amphotericin B/nystatin Amphotericin B/nystatin

Mechanism of action of Antimicrobial Agents Inhibition of protein synthesis Inhibition of protein synthesis Inhibition of protein synthesis Inhibition of protein synthesis Aminoglycosides Aminoglycosides Tetracyclines Tetracyclines Chloramphenicol Chloramphenicol Macrolides Macrolides Clindamycin Clindamycin

Mechanism of action of Antimicrobial Agents Mechanism of action of Antimicrobial Agents Interfering the metabolism of nucleotides and folic acid Interfering the metabolism of nucleotides and folic acid Rifampicin Rifampicin Quinolones Quinolones Sulfonamides Sulfonamides

Resistances of Bacteria Reasons Reasons Antibiotics abuse Antibiotics abuseAntibiotics abuseAntibiotics abuse Classification Classification Intrinsic resistance Intrinsic resistance Acquired resistance Acquired resistance

Antibiotics are routinely added to feed and water to prevent disease and to promote growth in food animals..

Mechanism of Bacterial Resistance Alteration of membrane permeability Alteration of membrane permeability Production of Inactivating Enzyme Production of Inactivating Enzyme β-lactamase β-lactamase Adenylase, phosphorylase, acetyltransferase Adenylase, phosphorylase, acetyltransferase Alteration of target for the drugs Alteration of target for the drugs Active efflux system Active efflux system Active efflux system Active efflux system Alteration of the metabolism route Alteration of the metabolism route

Bacterial resistance to antimicrobial agents ESBLs: extended spectrum β-Lactamases （超广谱 β- 内酰胺酶） ESBLs: extended spectrum β-Lactamases （超广谱 β- 内酰胺酶） P.aeruginosa （ 铜绿假单胞菌 ） P.aeruginosa （ 铜绿假单胞菌 ） MRSA: Methicillin resistant Staphylococcus aureus （耐甲氧西林的金黄色葡萄球菌） MRSA: Methicillin resistant Staphylococcus aureus （耐甲氧西林的金黄色葡萄球菌） VRE: Vancomycin resistant Enterococci （ 耐 万古霉素的肠球菌） VRE: Vancomycin resistant Enterococci （ 耐 万古霉素的肠球菌）

Principles of antibacterial use Basic principles Basic principles Diagnosis Diagnosis Rational use Rational use Newborn Newborn Pregnancy Pregnancy Elderly Elderly

Principles of antibacterial use Antimicrobial prophylaxis Antimicrobial prophylaxis Surgical prophylaxis Surgical prophylaxis Infectious endocarditis Infectious endocarditis Trauma, burn Trauma, burn operation operation Nonsurgical prophylaxis Nonsurgical prophylaxis Rheumatic fever Rheumatic fever Epidemic meningitis Epidemic meningitis Malaria, Tuberculosis Malaria, Tuberculosis

Principles of antibacterial use Antimicrobial agents combination Antimicrobial agents combination Drug categories Drug categories 1. β-Lactam antibiotics 2. Aminoglycosides 3. Tetracyclines, macrolide,chloramphenicol 4. Sulfonamides 1+2: Synergism 1+2: Synergism 1+3:antagonism 1+3:antagonism 2+3:synergism or plus 2+3:synergism or plus 3+4: plus 3+4: plus

Synergetic mechanism of combination antibacterial therapy Affect different component of the same mechanism Affect different component of the same mechanism Changing the permeability of the cytoplasmic membrane or the cell wall Changing the permeability of the cytoplasmic membrane or the cell wall Inhibiting the inactiving enzyme of antibacterial drugsInhibiting the different resistant microbial population Inhibiting the inactiving enzyme of antibacterial drugsInhibiting the different resistant microbial population

Rationale for combination antibacterial therapy  To Provide broad-spectrum empirical therapy in seriously ill patients  Serious infection that can not be controlled by one drug  To decrease the emergence of resistant strains  To decrease dose-related toxicity  Meningitis and osteomyelitis caused by bacterial infection

Principles of antibacterial use Misuse Misuse Virus infection Virus infection Unknown fever Unknown fever Topical use Topical use Improper prophylaxis and combination Improper prophylaxis and combination

Chapter 39 β-Lactam Antibiotics

Classification Penicillins Penicillins Penicillins Cephalosporins Cephalosporins Cephalosporins Other β-Lactam drugs Other β-Lactam drugs Carbapenems （碳青霉烯类） Carbapenems （碳青霉烯类） Cephamycins （头霉素类） Cephamycins （头霉素类） Oxacephalosporins （氧头孢烯类） Oxacephalosporins （氧头孢烯类） Monolactums （单环 β- 内酰胺类） Monolactums （单环 β- 内酰胺类） β-Lactamase inhibitors （ β- 内酰胺酶抑制剂） β-Lactamase inhibitors （ β- 内酰胺酶抑制剂）

Mechanism of action Mechanism of action Inhibition of bacterial cell wall synthesis Inhibition of bacterial cell wall synthesis Target: PBPs(penicillin-binding proteins) Target: PBPs(penicillin-binding proteins)PBPs Cell-wall autolytic enzyme Cell-wall autolytic enzyme

Mechanism of resistance Inactivation of drug by β-lactamase Inactivation of drug by β-lactamase Inactivation of drug by β-lactamase Inactivation of drug by β-lactamase Trapping mechanism Trapping mechanism Modification of PBPs Modification of PBPs Modification of PBPs Modification of PBPs Impaired penetration of drug to target PBPs Impaired penetration of drug to target PBPs Impaired penetration of drug to target PBPs Impaired penetration of drug to target PBPs Active efflux system Active efflux system Active efflux system Active efflux system Absence of autolysins Absence of autolysins

Penicillins History History Basic structure: 6-APA Basic structure: 6-APA Classification Classification Natural penicillins Natural penicillins Semisynthesized penicillins Semisynthesized penicillins

Penicillin G

Pharmacokinetics Absorption T 1/2 =0.5h~1h Absorption T 1/2 =0.5h~1h Distribution Distribution Excretion probenecid Excretion probenecid 90% tubular secretion 90% tubular secretion 10% glomerular filtration 10% glomerular filtration Benzathine benzyl penicillin Benzathine benzyl penicillin Procaine benzyl penicillin Procaine benzyl penicillin

Penicillin G Antimicrobial activity Antimicrobial activity Gram-positive cocci Gram-positive cocci Streptococci,pneumococci, staphylococci Streptococci,pneumococci, staphylococci Gram-positive rods Gram-positive rods Bacillus anthracis, diphtheriae, clostridium tetani Bacillus anthracis, diphtheriae, clostridium tetani Gram-negative cocci Gram-negative cocci Meningococci, diplococcus gonorrhoeae Meningococci, diplococcus gonorrhoeae Spirochete Spirochete 梅毒螺旋体, leptospira 梅毒螺旋体, leptospira

Clinical uses First choice for the following infections Infection caused by streptococci, pneumococci, meningococci etc Infection caused by streptococci, pneumococci, meningococci etc Infection caused by spirochetes Infection caused by spirochetes Infection caused by gram-positive rods Infection caused by gram-positive rods

Adverse reactions Allergic reactions Allergic reactions Common: Common: urticaria, fever, angioneurotic edema, eosinophilia, hemolytic anemia urticaria, fever, angioneurotic edema, eosinophilia, hemolytic anemia Severe: anaphylactic shock Severe: anaphylactic shock Herxheimer reaction Herxheimer reaction

Allergic reactions Allergic reactions  Reason :degraded products of penicillin  Prevention:  History of allergic reactions  Skin test  Epinephrine Adverse reactions

Semi-synthesized penicillins Acid-resistant penicillins Acid-resistant penicillins Penicillinase-resistant penicillins Penicillinase-resistant penicillins Extended-spectrum penicillins Extended-spectrum penicillins Extended-spectrum penicillins against P.aeruginosa Extended-spectrum penicillins against P.aeruginosa Penicillins against gram-negative bacteria Penicillins against gram-negative bacteria

Acid-resistant penicillins Drugs: penicillin V, phenethicillin ( 非奈西 林） Drugs: penicillin V, phenethicillin ( 非奈西 林） Character Character  Orally effective, not resist β-Lactamase  Lower potency than penicillin G Clinical uses: moderate infections Clinical uses: moderate infections Adverse reactions: allergic reaction Adverse reactions: allergic reaction

Penicillinase-resistant penicillins Drugs:methicillin ( 甲氧西林） oxacillin （苯唑西林）, cloxacillin （氯唑西林）, dicloxacillin （双氯西林） flucloxacillin ( 氟氯西林 ) Drugs:methicillin ( 甲氧西林） oxacillin （苯唑西林）, cloxacillin （氯唑西林）, dicloxacillin （双氯西林） flucloxacillin ( 氟氯西林 ) Character: acid-resistant/ penicillinase- resistant / lower potency than penicillin G Character: acid-resistant/ penicillinase- resistant / lower potency than penicillin G Clinical use Clinical use Infection caused by penicillin-resistant staphylococci Infection caused by penicillin-resistant staphylococci

Extended-spectrum penicillins Ampicillin, amoxicillin, pivampicillin Ampicillin, amoxicillin, pivampicillin Oral effective, susceptible to β-Lactamase Oral effective, susceptible to β-Lactamase Broad spectrum: G - / G + <penicillin Broad spectrum: G - / G + <penicillin No effect on P.aeruginosa No effect on P.aeruginosa Clinical uses: infection caused by gram-negative rods Clinical uses: infection caused by gram-negative rods

Extended-spectrum penicillins Ampicillin Ampicillin Not completely absorbed, F low Not completely absorbed, F low Effective on G - Effective on G - To G + : <penicillin To G + : <penicillin Clinical use: G - infection Clinical use: G - infection

Extended-spectrum penicillins Amoxycillin Amoxycillin Absorbed well, F high Absorbed well, F high G – infection G – infection Meningitis Meningitis Upper respiratory infection Upper respiratory infection Urinary tract infection Urinary tract infection H.p infection H.p infection

Extended-spectrum Penicillins against P.aeruginosa Carbenicillin, sulbencillin, ticarcillin, Carbenicillin, sulbencillin, ticarcillin, furbencillin, piperacillin, mezlocillin furbencillin, piperacillin, mezlocillin Character: Character: Wide spectrum and more activity on P.aeruginosa Wide spectrum and more activity on P.aeruginosa Not acid and β-lactamase resistant Not acid and β-lactamase resistant Usually in combination with aminoglycosides Usually in combination with aminoglycosides

Extended-spectrum Penicillins against P.aeruginosa Carbenicillin Carbenicillin High activity on G - and P.aeruginosa High activity on G - and P.aeruginosa Concentration in CSF is low Concentration in CSF is low Mainly used to treat P.aeruginosa infection in burn patients Mainly used to treat P.aeruginosa infection in burn patients Piperacillin Piperacillin Effective on anaerobes Effective on anaerobes Concentration in CSF is high Concentration in CSF is high

Penicillins against gram- negative bacteria Mecillinam （美西林）, temocillin （替莫西 林）, pivmecillinam （匹美西林） Mecillinam （美西林）, temocillin （替莫西 林）, pivmecillinam （匹美西林） Narrow-spectrum: mainly on G - rods Narrow-spectrum: mainly on G - rods β-Lactamase resistant β-Lactamase resistant No effect on P.aeruginosa No effect on P.aeruginosa Treatment of infections caused by G - rods Treatment of infections caused by G - rods

Cephalosporins Chemistry: 7-ACA Chemistry: 7-ACA Classification: four generations Classification: four generations  First-generation cephalosporins  Second- generation cephalosporins  Third-generation cephalosporins  Fourth- generation cephalosporins

First-generation cephalosporins Cefalothin 头孢噻吩 —— 先锋 I Cefalothin 头孢噻吩 —— 先锋 I Cefaloridine 头孢噻啶 —— 先锋 II Cefaloridine 头孢噻啶 —— 先锋 II Cefaloglycin 头孢来星 —— 先锋 III Cefaloglycin 头孢来星 —— 先锋 III Cefalexin 头孢氨苄 —— 先锋 IV Cefalexin 头孢氨苄 —— 先锋 IV Cefazolin 头孢唑啉 —— 先锋 V Cefazolin 头孢唑啉 —— 先锋 V Cefradine 头孢拉定 —— 先锋 VI Cefradine 头孢拉定 —— 先锋 VI Cefacetrile 头孢乙氰 —— 先锋 VII Cefacetrile 头孢乙氰 —— 先锋 VII Cefapirin 头孢匹林 —— 先锋 VIII Cefapirin 头孢匹林 —— 先锋 VIII Cefadroxil 头孢羟氨苄 Cefadroxil 头孢羟氨苄

First-generation cephalosporins Common characters: Common characters:  Activity on gram-positive bacteria: first>second>third  Activity on gram-negative bacteria: first<second<third  No effect on P. aeruginosa and anaerobes  Stability to β-Lactamase produced by gram- negative rods: first<second<third  Stable to β-Lactamase produced by gram-positive bacteria  Renal toxicity: first>second>third

First-generation cephalosporins Clinical uses Clinical uses Penicillin-resistant staphylococcal infection Penicillin-resistant staphylococcal infection Minor to moderate infections caused by sensitive bacteria Minor to moderate infections caused by sensitive bacteria

Second-generation cephalosporins Second-generation cephalosporins Drugs Drugs Cefamandole （头孢孟多）, Cefuroxime （ 头孢呋辛） Cefamandole （头孢孟多）, Cefuroxime （ 头孢呋辛） Cefaclor （头孢克洛，希刻劳） Cefaclor （头孢克洛，希刻劳）

Second-generation cephalosporins Common characters Common characters  More active on gram-negative bacteria  Less active on gram-positive bacteria  More stable to β-Lactamase produced by gram-negative rods  Some are effective on anaerobes  No effect on P. aeruginosa  Less renal toxicity

Second-generation cephalosporins Clinical uses Clinical uses Gram-negative bacteria infections ： first choice Gram-negative bacteria infections ： first choice Anaerobic infections Anaerobic infections

Third-generation cephalosporins Ceftriaxone （头孢曲松，罗氏芬） Ceftriaxone （头孢曲松，罗氏芬） Ceftazidime （头孢他定） Ceftazidime （头孢他定） Cefoperazone ( 头孢哌酮） Cefoperazone ( 头孢哌酮） Cefotaxime ( 头孢噻圬） Cefotaxime ( 头孢噻圬）

Third-generation cephalosporins Common characters Common characters Much more active on gram-negative bacteria Much more active on gram-negative bacteria To gram-positive bacteria: third<second<first To gram-positive bacteria: third<second<first Stable to extended β-Lactamase produced by gram-negative bacteria Stable to extended β-Lactamase produced by gram-negative bacteria Effective on anaerobes and P.aeruginosa Effective on anaerobes and P.aeruginosa No renal toxicity No renal toxicity Penetrating body fluids and tissues well Penetrating body fluids and tissues well

Third-generation cephalosporins Clinical uses Clinical uses a wide variety of serious infections caused by organisms that are resistant to most other drugs a wide variety of serious infections caused by organisms that are resistant to most other drugs

Fourth- generation cephalosporins Cefpirome （头孢匹罗）,cefepime （头孢吡圬）, cefclidin （头孢利定） Cefpirome （头孢匹罗）,cefepime （头孢吡圬）, cefclidin （头孢利定） Character: Character: Enhanced antimicrobial activity and broader spectrum Enhanced antimicrobial activity and broader spectrum Stable to most β-lactamase Stable to most β-lactamase More activity on gram-positive cocci More activity on gram-positive cocci Clinical uses: Clinical uses: infections caused by organisms that are resistant to third-generation cephalosporins infections caused by organisms that are resistant to third-generation cephalosporins

一、二、三代头孢作用比较 一代二代三代 G+G+G+G G-G-G-G 绿脓杆菌--有效 厌氧菌-有效有效 对  - 内酰胺 酶稳定性 G G 肾毒性+++-

Side effect of cephalosporins Allergic effect Allergic effect Gastrointestinal reactions Gastrointestinal reactions Renal toxicity Renal toxicity Other : bleeding Other : bleeding Disulfiram-like effect ( 双硫仑反应） Disulfiram-like effect ( 双硫仑反应）

Other β-Lactam drugs

Carbapenems （碳青霉烯类） The most important antimicrobial agents in 1990’s The most important antimicrobial agents in 1990’s Wide spectrum and high activity Wide spectrum and high activity Resistant to most β-Lactamase Resistant to most β-Lactamase (including ESBLs and cephalosporinase) (including ESBLs and cephalosporinase)

Carbapenems Thienamycin （硫霉素） Thienamycin （硫霉素） Imipenem （亚胺培南） Imipenem （亚胺培南） Imipenem-cilastatin:tienam （泰能） Imipenem-cilastatin:tienam （泰能） Meropenem （美罗培南） Meropenem （美罗培南） Panipenem （ 帕尼培南） Panipenem （ 帕尼培南）

Imipenem-cilastatin:tienam Susceptible to acid iv Susceptible to acid iv Treatment of severe infections Treatment of severe infections Contradications : Contradications : CNS disorder CNS disorder Baby less than 3 months Baby less than 3 months Renal dysfunction Renal dysfunction

Cephamycins （头霉素类） Cephamycins （头霉素类） Cefoxitin （头孢西丁） Cefoxitin （头孢西丁） Similar to second-generation cephalosporins Similar to second-generation cephalosporins More activity on anaerobes More activity on anaerobes β-Lactamase resistant High concentration in CSF High concentration in CSF Treatment of mixed anaerobic and aerobic infections Treatment of mixed anaerobic and aerobic infections

Oxacephalosporin （氧头孢烯类） Latamoxef （拉氧头孢）, Flomoxef （氟 氧头孢） Latamoxef （拉氧头孢）, Flomoxef （氟 氧头孢） Higher activity on anaerobes (especially Bacteroids fragilis) than third-generation cephalosporins Higher activity on anaerobes (especially Bacteroids fragilis) than third-generation cephalosporins Well resistant to manyβ-Lactamase Well resistant to manyβ-Lactamase Adverse reactions: PLT / d isulfiram-like effect Adverse reactions: PLT / d isulfiram-like effect

Monobactams Aztreonam （氨曲南）, carumonam （卡芦莫南） Aztreonam （氨曲南）, carumonam （卡芦莫南） No effect on gram-positive bacteria and anaerobes No effect on gram-positive bacteria and anaerobes High activity on gram-negative bacteria High activity on gram-negative bacteria No cross-allergic reaction with penicillin No cross-allergic reaction with penicillin Penicillin-allergic patients tolerate well Penicillin-allergic patients tolerate well Low toxicity Low toxicity

β-Lactamase inhibitors Clavulanic acid Clavulanic acid Sulbactam Sulbactam tazobactam tazobactam

β-Lactamase inhibitors Weak antimicrobial action Weak antimicrobial action Protect β-lactams from inactivation by β-lactamase Protect β-lactams from inactivation by β-lactamase Synergism Synergism Compound preparation ( 复方制剂） Compound preparation ( 复方制剂）

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