Chapter 38Chapter 38

Introduction To Introduction To Chemotherapeutic Drugs Chemotherapeutic Drugs

Brief History of Brief History of Chemotherapeutic DrugsChemotherapeutic Drugs

1910 1910 EhrlichEhrlich Arsphnamine( Arsphnamine( 砷凡纳明砷凡纳明 ) ) chechemotherapymotherapy

1929 1929 Fleming Fleming 1940 Florey 1940 Florey and Chainand Chain PenicilinPenicilin 1935 1935 Domagk Domagk Prontosil Prontosil （百浪多息）（百浪多息） 1960’s β-Lactam antibiotics1960’s β-Lactam antibiotics 1970’s Fluoroquinolones 1970’s Fluoroquinolones 1980’s New Macrolides1980’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 , Relationship between pathogen , chemotherapeutic drugs and patientschemotherapeutic drugs and patients

host

Antimicrobial agents mycrobacterium

Sid

e eff

ect

pro

cess

resistance

Antimicrobial action

pathogenicity

imm

unity

Several Terms related to ChemotherapySeveral Terms related to Chemotherapy Antimicrobial drugs(Antibacterial drugs, antifungal drugAntimicrobial drugs(Antibacterial drugs, antifungal drug

s, antiviral drugs) s, antiviral drugs) Chemotherapy Chemotherapy Antibacterial drugs Antibacterial drugs AntibioticsAntibiotics Antibacterial spectrum Antibacterial spectrum Antibacterial activityAntibacterial activity Minimal inhibitory concentration (MIC)Minimal inhibitory concentration (MIC) Minimal bactericidal concentration (MBC)Minimal bactericidal concentration (MBC) Bacteriostatic drugsBacteriostatic drugs Bactericidal drugsBactericidal drugs Chemotherapeutic index(CI)Chemotherapeutic index(CI) Post-antibiotic effect ( PAE )Post-antibiotic effect ( PAE )

Mechanism of action of the Mechanism of action of the Antibacterial AgentsAntibacterial Agents

Inhibiting the biosynthesis of the cell wallInhibiting the biosynthesis of the cell wall β-lactamβ-lactam

Increasing the permeability of the cytoplasmiIncreasing the permeability of the cytoplasmic membranec membrane AminoglycosidesAminoglycosides Imidazoles(miconazole, ketoconazole)Imidazoles(miconazole, ketoconazole) PolymixinsPolymixins Amphotericin B/nystatinAmphotericin B/nystatin

Mechanism of action of Mechanism of action of Antimicrobial AgentsAntimicrobial Agents

Inhibition of protein synthesisInhibition of protein synthesis AminoglycosidesAminoglycosides TetracyclinesTetracyclines Chloramphenicol Chloramphenicol Macrolides Macrolides Clindamycin Clindamycin

Mechanism of action of Mechanism of action of Antimicrobial AgentsAntimicrobial Agents

Interfering the metabolism of nuclInterfering the metabolism of nucleotides and folic acideotides and folic acid RifampicinRifampicin QuinolonesQuinolones Sulfonamides Sulfonamides

Resistances of BacteriaResistances of Bacteria

Reasons Reasons Antibiotics abuseAntibiotics abuse

ClassificationClassification Intrinsic resistance Intrinsic resistance Acquired resistanceAcquired resistance

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

Mechanism of Bacterial ResistanceMechanism of Bacterial Resistance

Alteration of membrane permeabilityAlteration of membrane permeability

Production of Inactivating EnzymeProduction of Inactivating Enzyme β-lactamaseβ-lactamase Adenylase, phosphorylase, acetyltransferaseAdenylase, phosphorylase, acetyltransferase

Alteration of target for the drugsAlteration of target for the drugs Active efflux systemActive efflux system Alteration of the metabolism routeAlteration of the metabolism route

Bacterial resistance to Bacterial resistance to antimicrobial agentsantimicrobial agents

ESBLs: ESBLs: extended spectrum β-Lactamasesextended spectrum β-Lactamases （超广（超广谱谱 β-β- 内酰胺酶）内酰胺酶）

P.aeruginosaP.aeruginosa （（铜绿假单胞菌铜绿假单胞菌）） MRSA: MRSA: Methicillin resistant Staphylococcus aureMethicillin resistant Staphylococcus aure

usus （耐甲氧西林的金黄色葡萄球菌）（耐甲氧西林的金黄色葡萄球菌） VRE: Vancomycin resistant EnterococciVRE: Vancomycin resistant Enterococci

（（耐万古霉素的肠球菌）耐万古霉素的肠球菌）

Principles of antibacterial usePrinciples of antibacterial use

Basic principlesBasic principles Diagnosis Diagnosis Rational useRational use

NewbornNewborn Pregnancy Pregnancy ElderlyElderly

Principles of antibacterial usePrinciples of antibacterial use

Antimicrobial prophylaxisAntimicrobial prophylaxis Surgical prophylaxisSurgical prophylaxis

Infectious endocarditisInfectious endocarditis Trauma, burnTrauma, burn operationoperation

Nonsurgical prophylaxisNonsurgical prophylaxis Rheumatic feverRheumatic fever Epidemic meningitisEpidemic meningitis Malaria, TuberculosisMalaria, Tuberculosis

Principles of antibacterial usePrinciples of antibacterial use

Antimicrobial agents combinationAntimicrobial agents combination Drug categoriesDrug categories

1.1.β-Lactam antibioticsβ-Lactam antibiotics2. Aminoglycosides2. Aminoglycosides3. Tetracyclines, macrolide ,chloramphenicol3. Tetracyclines, macrolide ,chloramphenicol4. Sulfonamides4. Sulfonamides

1+2: Synergism1+2: Synergism 1+3:antagonism1+3:antagonism 2+3:synergism or plus2+3:synergism or plus 3+4: plus3+4: plus

Synergetic mechanism ofSynergetic mechanism of combination antibacterial therapycombination antibacterial therapy

Affect different component of the same mecAffect different component of the same mechanismhanism

Changing the permeability of the cytoplasChanging the permeability of the cytoplasmic membrane or the cell wallmic membrane or the cell wall

Inhibiting the inactiving enzyme of antibactInhibiting the inactiving enzyme of antibacterial drugsInhibiting the different resistant erial drugsInhibiting the different resistant microbial populationmicrobial population

Rationale for combination Rationale for combination antibacterial therapyantibacterial therapy

To Provide broad-spectrum empirical therapTo Provide broad-spectrum empirical therapy in seriously ill patientsy in seriously ill patients

Serious infection that can not be controlled by Serious infection that can not be controlled by one drugone drug

To decrease the emergence of resistant strainsTo decrease the emergence of resistant strains To decrease dose-related toxicityTo decrease dose-related toxicity Meningitis and osteomyelitis caused by bacterMeningitis and osteomyelitis caused by bacter

ial infectionial infection

Principles of antibacterial usePrinciples of antibacterial use

MisuseMisuse Virus infectionVirus infection Unknown feverUnknown fever Topical useTopical use Improper prophylaxis and combination Improper prophylaxis and combination

Chapter 39Chapter 39β-Lactam β-Lactam

AntibioticsAntibiotics

ClassificationClassification PenicillinsPenicillins CephalosporinsCephalosporins Other β-Lactam drugsOther β-Lactam drugs

CarbapenemsCarbapenems （碳青霉烯类）（碳青霉烯类） CephamycinsCephamycins （头霉素类）（头霉素类） Oxacephalosporins Oxacephalosporins （氧头孢烯类）（氧头孢烯类） MonolactumsMonolactums （单环（单环 β-β- 内酰胺类）内酰胺类） β-Lactamase inhibitorsβ-Lactamase inhibitors （ （ β-β- 内酰胺酶抑制剂）内酰胺酶抑制剂）

Mechanism of actionMechanism of action

Inhibition of bacterial cell wall syInhibition of bacterial cell wall synthesisnthesis Target: PBPs(penicillin-binding prTarget: PBPs(penicillin-binding pr

oteins)oteins) Cell-wall autolytic enzymeCell-wall autolytic enzyme

Mechanism of resistanceMechanism of resistance Inactivation of drug by β-lactamaseInactivation of drug by β-lactamase Trapping mechanismTrapping mechanism Modification of PBPsModification of PBPs Impaired penetration of drug to target PImpaired penetration of drug to target P

BPsBPs Active efflux systemActive efflux system Absence of autolysinsAbsence of autolysins

PenicillinsPenicillins HistoryHistory Basic structure: 6-APABasic structure: 6-APA ClassificationClassification

Natural penicillinsNatural penicillins Semisynthesized penicillinsSemisynthesized penicillins

Penicillin GPenicillin G

PharmacokineticsPharmacokinetics Absorption TAbsorption T1/21/2=0.5h~1h=0.5h~1h DistributionDistribution Excretion Excretion probenecidprobenecid

90% tubular secretion90% tubular secretion 10% glomerular filtration10% glomerular filtration

Benzathine benzyl penicillinBenzathine benzyl penicillin Procaine benzyl penicillinProcaine benzyl penicillin

Penicillin GPenicillin G Antimicrobial activityAntimicrobial activity

Gram-positive cocciGram-positive cocci Streptococci ,Streptococci ,pneumococci , staphylococcipneumococci , staphylococci

Gram-positive rodsGram-positive rods Bacillus anthracis, diphtheriae, clostridium tetaBacillus anthracis, diphtheriae, clostridium teta

niniGram-negative cocciGram-negative cocci

Meningococci, diplococcus gonorrhoeaeMeningococci, diplococcus gonorrhoeae

SpirocheteSpirochete梅毒螺旋体梅毒螺旋体 , leptospira, leptospira

Clinical usesClinical usesFirst choice for the following infectionsFirst choice for the following infections Infection caused by streptococci, pneuInfection caused by streptococci, pneu

mococci, meningococci etcmococci, meningococci etc Infection caused by spirochetesInfection caused by spirochetes Infection caused by gram-positive rodsInfection caused by gram-positive rods

Adverse reactionsAdverse reactionsAllergic reactionsAllergic reactions

Common: Common:

urticaria, fever, angioneurotic edema, urticaria, fever, angioneurotic edema, eosinophilia, hemolytic anemiaeosinophilia, hemolytic anemia

Severe: anaphylactic shockSevere: anaphylactic shockHerxheimer reactionHerxheimer reaction

Allergic reactionsAllergic reactions ReasonReason:degraded products of penicillin:degraded products of penicillin PreventionPrevention::

History of allergic reactionsHistory of allergic reactions Skin testSkin test EpinephrineEpinephrine

Adverse reactionsAdverse reactions

Semi-synthesized penicillinsSemi-synthesized penicillins Acid-resistant penicillinsAcid-resistant penicillins Penicillinase-resistant penicillinsPenicillinase-resistant penicillins Extended-spectrum penicillinsExtended-spectrum penicillins Extended-spectrum penicillins against Extended-spectrum penicillins against

P.aeruginosaP.aeruginosa Penicillins against gram-negative bactePenicillins against gram-negative bacte

riaria

Acid-resistant penicillinsAcid-resistant penicillins DrugsDrugs: penicillin V, phenethicillin: penicillin V, phenethicillin(( 非奈西非奈西

林）林）

CharacterCharacter Orally effective, not resist β-LactamaseOrally effective, not resist β-Lactamase Lower potency than penicillin GLower potency than penicillin G

• Clinical usesClinical uses: moderate infections: moderate infections• Adverse reactionsAdverse reactions: allergic reaction: allergic reaction

Penicillinase-resistant penicilliPenicillinase-resistant penicillinsns

DrugsDrugs::methicillinmethicillin(( 甲氧西林）甲氧西林） oxacillinoxacillin （苯唑西林）（苯唑西林） , , cloxacillincloxacillin （氯唑西林）（氯唑西林） , dicloxacillin, dicloxacillin （双氯西林）（双氯西林） fluflucloxacillincloxacillin(( 氟氯西林氟氯西林 ))

Character: Character: acid-resistant/acid-resistant/ penicillinase-resistapenicillinase-resistant / lower potency than penicillin Gnt / lower potency than penicillin G

Clinical useClinical use Infection caused by penicillin-resistant staphylInfection caused by penicillin-resistant staphyl

ococciococci

Extended-spectrum penicillinsExtended-spectrum penicillins

Ampicillin, amoxicillin, pivampicillinAmpicillin, amoxicillin, pivampicillin Oral effective, susceptible to β-LactamaseOral effective, susceptible to β-Lactamase Broad spectrum: Broad spectrum: GG-- / G / G++ <penicillin <penicillin

No effect on No effect on P.aeruginosaP.aeruginosa Clinical uses: Clinical uses: infection caused by grainfection caused by gra

m-negative rodsm-negative rods

Extended-spectrum penicillinsExtended-spectrum penicillins

AmpicillinAmpicillin Not completely absorbed , F lowNot completely absorbed , F low Effective on GEffective on G- -

To GTo G++: <penicillin: <penicillin Clinical use: GClinical use: G- - infectioninfection

Extended-spectrum penicillinsExtended-spectrum penicillins

AmoxycillinAmoxycillin Absorbed well , F highAbsorbed well , F high G G –– infection infection

Meningitis Meningitis Upper respiratory infectionUpper respiratory infection Urinary tract infectionUrinary tract infection H.p infectionH.p infection

Extended-spectrum Penicillins Extended-spectrum Penicillins against P.aeruginosaagainst P.aeruginosa

Carbenicillin, sulbencillin, ticarcillin,Carbenicillin, sulbencillin, ticarcillin,

furbencillin, piperacillin, mezlocillinfurbencillin, piperacillin, mezlocillin• Character: Character:

• Wide spectrum and more activity on P.aeruginosaWide spectrum and more activity on P.aeruginosa• Not acid and β-lactamase resistantNot acid and β-lactamase resistant

• Usually in combination with aminoglycosidesUsually in combination with aminoglycosides

Extended-spectrum Penicillins agExtended-spectrum Penicillins against P.aeruginosaainst P.aeruginosa

CarbenicillinCarbenicillin High activity on GHigh activity on G- - andand P.aeruginosaP.aeruginosa Concentration in CSF is lowConcentration in CSF is low Mainly used to treat Mainly used to treat P.aeruginosa P.aeruginosa

infection in burn patientsinfection in burn patients PiperacillinPiperacillin

Effective on anaerobesEffective on anaerobes Concentration in CSF is highConcentration in CSF is high

Penicillins against gram-negaPenicillins against gram-negative bacteriative bacteria

MecillinamMecillinam （美西林）（美西林） , temocillin, temocillin （替莫西（替莫西林） 林） ,, pivmecillinampivmecillinam （匹美西林）（匹美西林）

Narrow-spectrum: mainly on GNarrow-spectrum: mainly on G-- rods rods β-Lactamase resistantβ-Lactamase resistant No effect on No effect on P.aeruginosaP.aeruginosa Treatment of infections caused by GTreatment of infections caused by G- - roro

dsds

CephalosporinsCephalosporins Chemistry: 7-ACAChemistry: 7-ACA Classification: four generationsClassification: four generations

First-generation cephalosporinsFirst-generation cephalosporinsSecond- generation cephalosporinsSecond- generation cephalosporinsThird-generation cephalosporinsThird-generation cephalosporinsFourth- generation cephalosporinsFourth- generation cephalosporins

First-generation cephalosporinsFirst-generation cephalosporins Cefalothin Cefalothin 头孢噻吩——先锋头孢噻吩——先锋 II Cefaloridine Cefaloridine 头孢噻啶——先锋头孢噻啶——先锋 IIII CefaloglycinCefaloglycin 头孢来星——先锋头孢来星——先锋 IIIIII Cefalexin Cefalexin 头孢氨苄——先锋头孢氨苄——先锋 IVIV Cefazolin Cefazolin 头孢唑啉——先锋头孢唑啉——先锋 VV Cefradine Cefradine 头孢拉定——先锋头孢拉定——先锋 VIVI Cefacetrile Cefacetrile 头孢乙氰——先锋头孢乙氰——先锋 VIIVII Cefapirin Cefapirin 头孢匹林——先锋头孢匹林——先锋 VIIIVIII CefadroxilCefadroxil 头孢羟氨苄头孢羟氨苄

First-generation cephalosporinsFirst-generation cephalosporins Common characters:Common characters:

Activity on gram-positive bacteria: first>second>thiActivity on gram-positive bacteria: first>second>thirdrd

Activity on gram-negative bacteria: first<second<thiActivity on gram-negative bacteria: first<second<thirdrd

No effect on P. aeruginosa and anaerobes No effect on P. aeruginosa and anaerobes Stability to β-Lactamase produced by gram-negative Stability to β-Lactamase produced by gram-negative

rods: first<second<thirdrods: first<second<third Stable to β-Lactamase produced by gram-positive bacStable to β-Lactamase produced by gram-positive bac

teriateria Renal toxicity: first>second>thirdRenal toxicity: first>second>third

First-generation First-generation cephalosporinscephalosporins

Clinical usesClinical uses• Penicillin-resistant staphylococcal Penicillin-resistant staphylococcal

infectioninfection• Minor to moderate infections caused by Minor to moderate infections caused by

sensitive bacteriasensitive bacteria

Second-generation Second-generation cephalosporins cephalosporins

DrugsDrugs

CefamandoleCefamandole （头孢孟多）（头孢孟多） ,, Cefuro Cefuroximexime （（头孢呋辛）头孢呋辛）

CefaclorCefaclor （头孢克洛，希刻劳）（头孢克洛，希刻劳）

Second-generation Second-generation cephalosporins cephalosporins

Common charactersCommon characters More active on gram-negative bacteriaMore active on gram-negative bacteriaLess active on gram-positive bacteriaLess active on gram-positive bacteria More stable to β-Lactamase produced by grMore stable to β-Lactamase produced by gr

am-negative rodsam-negative rods Some are effective on anaerobesSome are effective on anaerobesNo effect on No effect on P. aeruginosaP. aeruginosa Less renal toxicityLess renal toxicity

Second-generation Second-generation cephalosporinscephalosporins

Clinical usesClinical uses• Gram-negative bacteria infectionsGram-negative bacteria infections ：：

first choicefirst choice• Anaerobic infectionsAnaerobic infections

Third-generation Third-generation cephalosporinscephalosporins

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

Third-generation cephalosporiThird-generation cephalosporinsns

Common charactersCommon characters• Much more active on gram-negative bacteriaMuch more active on gram-negative bacteria• To gram-positive bacteria: third<second<firstTo gram-positive bacteria: third<second<first• Stable to extended β-Lactamase produced by grStable to extended β-Lactamase produced by gr

am-negative bacteriaam-negative bacteria• Effective on anaerobes and P.aeruginosaEffective on anaerobes and P.aeruginosa• No renal toxicityNo renal toxicity• Penetrating body fluids and tissues wellPenetrating body fluids and tissues well

Third-generation Third-generation cephalosporinscephalosporins

Clinical usesClinical uses

a wide variety of a wide variety of serious infectionsserious infections caused by organisms that are caused by organisms that are resistant to most other drugsresistant to most other drugs

Fourth- generation Fourth- generation cephalosporinscephalosporins

CefpiromeCefpirome （头孢匹罗）（头孢匹罗） ,cefepime,cefepime （头孢吡圬）（头孢吡圬） , , cefclidincefclidin （头孢利定）（头孢利定）

Character:Character:

• Enhanced antimicrobial activity and broader spEnhanced antimicrobial activity and broader spectrumectrum

• Stable to most β-lactamaseStable to most β-lactamase

• More activity on gram-positive cocciMore activity on gram-positive cocci

• Clinical uses:Clinical uses:

• infections caused by organisms that are infections caused by organisms that are resistantresistant to third-generation cephalosporinsto third-generation cephalosporins

一、二、三代头孢作用比较一代一代 二代二代 三代三代

GG++ ++++++ ++++ ++

GG-- ++ ++++ ++++++

绿脓杆菌绿脓杆菌 -- -- 有效有效厌氧菌厌氧菌 -- 有效有效 有效有效对对 -- 内酰内酰胺酶稳定胺酶稳定性性

GG+ + ++++++

GG-- - -

++++++

++++++++++

++++++

肾毒性肾毒性 ++++ ++ --

Side effect of cephalosporinsSide effect of cephalosporins

Allergic effectAllergic effect Gastrointestinal reactionsGastrointestinal reactions Renal toxicityRenal toxicity Other : bleeding Other : bleeding Disulfiram-like effectDisulfiram-like effect(( 双硫仑反应）双硫仑反应）

Other β-Lactam drugs

CarbapenemsCarbapenems （碳青霉烯（碳青霉烯类）类）

The most important antimicrobial agents iThe most important antimicrobial agents in 1990’sn 1990’s

Wide spectrum and high activityWide spectrum and high activity Resistant to most β-LactamaseResistant to most β-Lactamase

(including ESBLs and cephalosporinase)(including ESBLs and cephalosporinase)

CarbapenemsCarbapenemsThienamycinThienamycin （硫霉素）（硫霉素） ImipenemImipenem （亚胺培南）（亚胺培南） Imipenem-cilastatin:tienamImipenem-cilastatin:tienam （泰（泰

能）能）MeropenemMeropenem （美罗培南）（美罗培南）PanipenemPanipenem （（帕尼培南）帕尼培南）

Imipenem-cilastatin:tienamImipenem-cilastatin:tienam

Susceptible to acid ivSusceptible to acid iv Treatment of severe infectionsTreatment of severe infections ContradicationsContradications::

CNS disorderCNS disorder Baby less than 3 monthsBaby less than 3 months Renal dysfunctionRenal dysfunction

Cephamycins Cephamycins （头霉素（头霉素

类）类） CefoxitinCefoxitin （头孢西丁）（头孢西丁）

Similar to second-generation cephalosporinsSimilar to second-generation cephalosporins More activity on anaerobesMore activity on anaerobes β-Lactamase resistant High concentration in CSF High concentration in CSF Treatment of mixed anaerobic and aerobic infectiTreatment of mixed anaerobic and aerobic infecti

onsons

OxacephalosporinOxacephalosporin （氧头孢烯（氧头孢烯类）类）

LatamoxefLatamoxef （拉氧头孢）（拉氧头孢） , Flomoxef, Flomoxef （氟（氟氧头孢）氧头孢）

Higher activity on anaerobes (especially Higher activity on anaerobes (especially Bacteroids fragilis) than third-generation Bacteroids fragilis) than third-generation cephalosporinscephalosporins

Well resistant to manyβ-LactamaseWell resistant to manyβ-Lactamase Adverse reactions: PLT / dAdverse reactions: PLT / disulfiram-like efisulfiram-like ef

fectfect

MonobactamsMonobactams AztreonamAztreonam （氨曲南）（氨曲南） , carumonam, carumonam （卡芦莫（卡芦莫

南）南） No effect on gram-positive bacteria and aNo effect on gram-positive bacteria and a

naerobesnaerobes High activity on gram-negative bacteriaHigh activity on gram-negative bacteria No cross-allergic reaction with penicillinNo cross-allergic reaction with penicillin Penicillin-allergic patients tolerate wellPenicillin-allergic patients tolerate well Low toxicityLow toxicity

β-Lactamase inhibitorsβ-Lactamase inhibitors

Clavulanic acid Clavulanic acid SulbactamSulbactam tazobactamtazobactam

β-Lactamase inhibitorsβ-Lactamase inhibitors

Weak antimicrobial actionWeak antimicrobial action Protect β-lactams from inactivation bProtect β-lactams from inactivation b

y β-lactamasey β-lactamase SynergismSynergism Compound preparation Compound preparation (( 复方制剂）复方制剂）

flory

florey chain