macrolides, lincomycins &vancomycins section 3 yun-bi lu, phd 卢韵碧 dept. of pharmacology,...

Macrolides, Macrolides, Lincomycins &VancomycinsLincomycins &Vancomycins

Section 3Section 3

Yun-Bi Lu, PhDYun-Bi Lu, PhD卢韵碧卢韵碧

Dept. of Pharmacology, Dept. of Pharmacology, School of Medicine, Zhejiang UniversitySchool of Medicine, Zhejiang University

[email protected]@zju.edu.cn

• Erythromycin (Erythromycin ( 红霉素红霉素 ))

• Clarithromycin (Clarithromycin ( 克拉霉克拉霉素素 ))

• Azithromycin (Azithromycin ( 阿奇霉素阿奇霉素 ))

• Telithromycin(Telithromycin( 泰利霉素泰利霉素 ))

Part APart A Macrolides Macrolides

14 member rings14 member rings



1. 1. AntimicrobialAntimicrobial spectrum spectrum：：• GG++ organisms organisms• GG-- cocci: cocci: Streptococcus pyogenes and pnStreptococcus pyogenes and pn

eumoniae eumoniae • Mycoplasma pneumoniae(pneumoniae( 肺支原体肺支原体 ) and ) and

Legionnella (Legionnella ( 军团菌军团菌 ))etcetc. 2. 2. Antimicrobial activity:Antimicrobial activity: • bactericidal and bacteriostatic,bactericidal and bacteriostatic, depending on the concentration. depending on the concentration. • more active at alkalinemore active at alkaline

General properties of General properties of MacrolidesMacrolides

3. Mechanism of action: 3. Mechanism of action:

macrolidemacrolidesubunitsubunit

4. Mechanism of resistance: 4. Mechanism of resistance:

• modification of the ribosomal binding sitemodification of the ribosomal binding site

• production of esterase that hydrolyze macproduction of esterase that hydrolyze mac

rolides.rolides.• reduced permeability of cell membrane orreduced permeability of cell membrane or active effluxactive efflux system is involved.system is involved.

• Cross-resistance is complete betweenCross-resistance is complete between erythromycin and the other macrolides.erythromycin and the other macrolides.

4. ADME4. ADME

1) 1) AAbsorption: bsorption:

Stearate and ester of erythromycin Stearate and ester of erythromycin

are fairly acid-resistant and somewhare fairly acid-resistant and somewh

at batter absorbed. Food interferes wat batter absorbed. Food interferes w

ith absorption. ith absorption.


4. ADME4. ADME

2) 2) DDistribution: does not cross BBB.istribution: does not cross BBB.

3) 3) EElimination: it is concentrated in the limination: it is concentrated in the

liver, where some is unactived, while liver, where some is unactived, while

some is excreted in active form in thsome is excreted in active form in th

e bile.e bile.


5.Clinical Uses:5.Clinical Uses:

1) Mycoplasma (1) Mycoplasma ( 支原体支原体 ) infections.) infections. 2) Legionnaire’s disease 2) Legionnaire’s disease ((军团菌病军团菌病 )). . 3) Chlamydia infections 3) Chlamydia infections ((衣原体感染衣原体感染 )).. 4) Streptococcus 4) Streptococcus ((链球菌链球菌 )) infections. infections. 5) Diphtheria 5) Diphtheria ((白喉白喉 ), ), chincoughchincough ((百日百日咳咳 ).).

6) toxoplasmosis(6) toxoplasmosis( 弓形虫病弓形虫病 ).).


6.Adverse response:6.Adverse response:

1) GI Effects: nausea, vomiting, abdomina1) GI Effects: nausea, vomiting, abdomina

l cramps(l cramps( 痉挛痉挛 )…)…

2) Liver Toxicity: Cholestatic hepatitis2) Liver Toxicity: Cholestatic hepatitis

((胆汁淤积性肝炎胆汁淤积性肝炎 ).).

3) Cardiotoxic effects 3) Cardiotoxic effects

4) Auditory impairment (Ototoxicity)4) Auditory impairment (Ototoxicity)

Hypersensitivity reactionsHypersensitivity reactions

SuperinfectionsSuperinfections


7. Drug interactions7. Drug interactions

• Erythromycin metabolites can iErythromycin metabolites can inhibit cytochrome P450 enzyme.nhibit cytochrome P450 enzyme.


• Erythromycin (Erythromycin ( 红霉素红霉素 ))

• Clarithromycin (Clarithromycin ( 克拉霉克拉霉素素 ))

• Azithromycin (Azithromycin ( 阿奇霉素阿奇霉素 ))

• Telithromycin(Telithromycin( 泰利霉素泰利霉素 ))

MacrolidesMacrolides

• Lincomycin (Lincomycin ( 林可霉素林可霉素 ))

• Clindamycin (Clindamycin ( 克林霉素克林霉素 ))

Part B Part B Lincomycin & ClindamycinLincomycin & Clindamycin

Antimicrobial propertiesAntimicrobial properties

• resemble erythromycin in resemble erythromycin in antibacterial spectrum, antibacterial spectrum, activity, mechanism and activity, mechanism and resistance.resistance.

Lincomycin & ClindamycinLincomycin & Clindamycin

Mechanism of action:Mechanism of action:

①①ChloramphenicolChloramphenicol

②②Macrolides, ClindMacrolides, Clindamycinamycin

③③TetracyclinesTetracyclines

PharmacokineticsPharmacokinetics

• about 90% protein-boundabout 90% protein-bound• excretion excretion viavia the liver,bile, and the liver,bile, and

urine urine • penetrate well into most tissue, penetrate well into most tissue,

including bone, but not CSF. including bone, but not CSF.


Clinical UsesClinical Uses

• severe anaerobic infection severe anaerobic infection • aerobic Gaerobic G++ cocci infection cocci infection• combination with pyrimethamine (combination with pyrimethamine ( 乙胺嘧啶乙胺嘧啶 ) )

for AIDS-related toxoplasmosisfor AIDS-related toxoplasmosis （弓形体病）（弓形体病）• combination with primaquine (combination with primaquine ( 伯氨喹伯氨喹 ) for A) for A

IDS-related IDS-related pneumocystis carinii pneumocystis carinii pneumoniapneumonia（肺囊虫性肺炎）（肺囊虫性肺炎） . .


Adverse response:Adverse response:

1) GI effects: Antibiotic-associated co1) GI effects: Antibiotic-associated colitis litis ((pseudomembranous colitispseudomembranous colitis 伪伪膜性结肠炎膜性结肠炎 ))..

2) allergic reaction2) allergic reaction3) impaired liver function3) impaired liver function


Vancomycin (Vancomycin ( 万古霉素万古霉素 ))

Norvancomycin (Norvancomycin ( 去甲万古霉素去甲万古霉素 ))

Teicoplanin (Teicoplanin ( 替考拉宁，太古霉素替考拉宁，太古霉素 ))

VancomycinsVancomycins

Antibacterial activityAntibacterial activity

bactericidal for Gbactericidal for G++ bacteria bacteria ( especially G( especially G++ ococci, includin ococci, includin

g MRSA & MRSE) g MRSA & MRSE)


• Antibacterial MechanismAntibacterial Mechanism

Inhibiting cell wall synthesis by bindinInhibiting cell wall synthesis by binding to the g to the DD-Ala--Ala-DD-Ala terminus of nasc-Ala terminus of nascent peptidoglycan penta-peptide. ent peptidoglycan penta-peptide.

• Resistance Resistance occurred because of the alteration of occurred because of the alteration of

DD-Ala--Ala-DD-Ala to the -Ala to the DD-Ala--Ala-DD-Ser. -Ser.


Fig. Antibacterial MechanismFig. Antibacterial Mechanism of Vancomycins of Vancomycins

• ADMEADME

• Oral administration (poorly absorbed).Oral administration (poorly absorbed).

• Intravenous administration, is excreted by glIntravenous administration, is excreted by gl

omerular filtration (accumulates when renal fuomerular filtration (accumulates when renal fu

nction is impaired).nction is impaired).

• Widely distributed in the body, including CSF Widely distributed in the body, including CSF

when the meninges is inflamed. when the meninges is inflamed.


• Clinical UsesClinical Uses1) severe infection caused by MRSA 1) severe infection caused by MRSA etcetc..2) alternative for 2) alternative for -lactam -lactam 3) enterococcal or staphyococcal endoca3) enterococcal or staphyococcal endoca

rditis (combination with gentamicin).rditis (combination with gentamicin).4) pseudomembranous colitis4) pseudomembranous colitis


Pseudomembranous enterocolitis

Hurley and Ngueyn Arch Intern Med. 2002;162:2177-2184.

Pseudomembranous colitis.

Endoscopic en face view of colon wall demonstrating several pseudomembranes (arrows).

http://archinte.ama-assn.org/cgi/content/full/162/19/2177/FIGIRA10073F3

Focal ulceration can be seen at the tips of the mucosa. The exudate of fibrin and inflammatory tissue.

Pseudomembranous enterocolitis

Normal

• Adverse ReactionsAdverse Reactions

1) Hypersensitive reaction1) Hypersensitive reaction (e.g. red man syndrome)(e.g. red man syndrome)2) Ototoxicity2) Ototoxicity3) Nephrotoxicity3) Nephrotoxicity4) G4) Gl effects, l effects, etcetc..


Aminoglycosides & polymyxinsAminoglycosides & polymyxins

Section 4Section 4

• History and Source : History and Source : the research madthe research made by Waksman and coworks within 19e by Waksman and coworks within 1939-194339-1943

• Clinical Applications: Clinical Applications: for the treatmenfor the treatment of aerobic Gt of aerobic G-- bacterial infections and bacterial infections and tuberculosistuberculosis

• Two classes:Two classes: crude product and crude product and semisynthetic derivative semisynthetic derivative

OverviewOverview

Part APart A Aminoglycosides Aminoglycosides

AminoglycosidesAminoglycosides

1. 1. Antimicrobial activity:Antimicrobial activity:

i) rapidly bactericidal to resting i) rapidly bactericidal to resting bacterium bacterium

ii) broad-spectrum ii) broad-spectrum

iii) more active at alkalineiii) more active at alkaline

General propertiesGeneral properties


iv) iv) concentration-dependent activityconcentration-dependent activity

v) v) the duration of post antibiotic effect (PAE) is the duration of post antibiotic effect (PAE) is cconcentration- dependent oncentration- dependent ((10 hours).10 hours).

vi) first exposure effect (FEE)vi) first exposure effect (FEE)


Blood Concentration

MIC

Peak Concentration

Time (h)

Bacterial growth is inhibited long after concentration below the MIC

2. 2. AntimicrobialAntimicrobial spectrum spectrum ：：

• aerobicaerobic GG-- bacilli and coccibacilli and cocci

• aerobicaerobic GG++ organisms organisms

• Streptomycin and kanamycin are alsStreptomycin and kanamycin are also active against o active against Mycobacterium tubeMycobacterium tuberculosisrculosis


3. 3. Mechanism of action:Mechanism of action:

• inhibit protein synthesis inhibit protein synthesis

• act as Ionic- sorbent, act directly on act as Ionic- sorbent, act directly on permeability of the cell membrane of permeability of the cell membrane of bacterium.bacterium.


•Blocks the initiation of protein synthesisBlocks the initiation of protein synthesis

Mechanism of action -Mechanism of action - inhibit protein synthesisinhibit protein synthesis


•Blocks the initiation of protein synthesisBlocks the initiation of protein synthesis

•Incorporation of incorrect amino acidIncorporation of incorrect amino acid



•Blocks further translocation and Blocks further translocation and elicits premature terminations elicits premature terminations

•disrupt the normal cycle of ribosomal, disrupt the normal cycle of ribosomal, make the ribosomal exhaustedmake the ribosomal exhausted


i) Interfering with the initiation complex of i) Interfering with the initiation complex of

peptide formation.peptide formation.

ii) Inducing misreading of mRNA, which causes ii) Inducing misreading of mRNA, which causes

the incorporation of incorrect amino acid into the incorporation of incorrect amino acid into

peptide, resulting nonfunctional or toxic peptide, resulting nonfunctional or toxic

protein. protein.


iii) causing breakup of polysomes intoiii) causing breakup of polysomes into

nonfunctional monosomes.nonfunctional monosomes.

iv) disrupt the normal cycle ofiv) disrupt the normal cycle of

ribosomal, make the ribosomal ribosomal, make the ribosomal

exhausted.exhausted.


Mechanism of resistanceMechanism of resistance

produces enzymesproduces enzymes

Altered ribosomal subunitAltered ribosomal subunit

Changes of PorinsChanges of Porins

Active efflux systemActive efflux system

i) The microorganism produces a transferase eni) The microorganism produces a transferase en

zyme or enzymes that inactivate the aminoglyczyme or enzymes that inactivate the aminoglyc

oside by adenylyation, acetylation, or phosphooside by adenylyation, acetylation, or phospho

rylation.rylation.

ii) Impaired entry of aminoglycoside into the cell.ii) Impaired entry of aminoglycoside into the cell.

iii) The receptor protein on the 30S ribosomal suiii) The receptor protein on the 30S ribosomal su

bunit may be deleted or altered as a result of bunit may be deleted or altered as a result of

mutation.mutation.

Mechanism of ResistanceMechanism of Resistance

ADMEADME

i) i) AAbsorption: not absorbed after po, but rapidlbsorption: not absorbed after po, but rapidly absorbed after IM, peak time 0.5-2h.y absorbed after IM, peak time 0.5-2h.

ii) ii) DDistribution: Binding to plasma protein is miistribution: Binding to plasma protein is minimal, do not enter cell, nor do they cross Bnimal, do not enter cell, nor do they cross BBB,but they cross the placenta, reach high cBB,but they cross the placenta, reach high concentrations in secretions and body fluids. oncentrations in secretions and body fluids. Tissue level is low expect in the cortex of kidTissue level is low expect in the cortex of kidney.ney.


ADME ADME iii) iii) EElimination: excreted mainly by glolimination: excreted mainly by glo

merular filtration. If renal function is imerular filtration. If renal function is impaired, accumulation occurs with a mpaired, accumulation occurs with a increase in those toxic effects which increase in those toxic effects which are dose related.are dose related.

TT1/21/2=2-3h=2-3h



• be mostly used against be mostly used against aerobicaerobic G-G- bacteria (bacteria (bacillbacill

ii, enteric) and in sepsis, be almost always used in , enteric) and in sepsis, be almost always used in

combination withcombination with-lactam antibiotic or fluoroqun-lactam antibiotic or fluoroqun

olones (olones ( 氟喹诺酮类氟喹诺酮类 ))

• against against aerobicaerobic G+G+ bacteria and in sepsis, be almbacteria and in sepsis, be alm

ost always used in combination with penicillins oost always used in combination with penicillins o

r vancomycinr vancomycin

• against against Mycobacterium tuberculosisMycobacterium tuberculosis


Adverse reactionsAdverse reactions

i) i) OtotoxicityOtotoxicity • involves progressive damage to and destruction of the involves progressive damage to and destruction of the

sensory cells in the cochlea and vestibular organ in the sensory cells in the cochlea and vestibular organ in the ear (ear (irreversible!!irreversible!! ). ).

Ototoxicity (Ototoxicity (cochleacochlea))• Kanamycin(1.6%)> Amikacin> Amikacin> Sisomicin> Gentamicin> Gentamicin>

Tobramycin(0.4%)Tobramycin(0.4%) Ototoxicity (Ototoxicity (vestibular organvestibular organ))• Kanamycin(4.7%)> Streptomycin> > Sisomicin> GentamiGentami

cin> Tobramycin(0.4%)cin> Tobramycin(0.4%)



ii) ii) NephrotoxicityNephrotoxicity

• consists of damage to the kidney tubules and bconsists of damage to the kidney tubules and be reversed if stop using.e reversed if stop using.

• Amikacin < Amikacin < Streptomycin or Tobramycin< Tobramycin< GentaGentamicin < micin < Kanamycin <Neomycin


Blue, high frequencyRed, low frequency

NephrotoxicityNephrotoxicity & OtotoxicityOtotoxicity


iii) iii) Neuromuscular blockade (paralysis)Neuromuscular blockade (paralysis)

• generally occurred after intra-pleural or intra-peritongenerally occurred after intra-pleural or intra-peritoneal instillation of large doses of an aminoglycosides eal instillation of large doses of an aminoglycosides

• Tobramycin < Gentamicin < Tobramycin < Gentamicin < Kanamycin or Amikacin Amikacin <<Streptomycin <Neomycin

• Calcium salt or inhibitor of cholinesterase (neostigmCalcium salt or inhibitor of cholinesterase (neostigmine) is the preferred treatment for this toxicity.ine) is the preferred treatment for this toxicity.



iv) iv) Allergic reactionAllergic reaction

• skin rashes fever, eosinophiliay skin rashes fever, eosinophiliay (( 嗜酸嗜酸粒细胞增多症）粒细胞增多症） , anaphylactic shock, , anaphylactic shock, etetc.c.


• Streptomycin Streptomycin （链霉素）（链霉素）• Gentamicin Gentamicin （庆大霉素）（庆大霉素）• TobramycinTobramycin （妥布霉素）（妥布霉素）• AmikacinAmikacin （阿米卡星）（阿米卡星）• NetilmicinNetilmicin （奈替米星）（奈替米星）• NeomycinNeomycin （新霉素）（新霉素）

Aminoglycosides Aminoglycosides agents

• Kanamycin(卡那霉素）• Arbekacin （阿贝卡星）• Dibekacin （地贝卡星）• Micronomicin（小诺米星）• Sisomicin（西索米星）• Etilmicin（依替米星）• Isepamicin（异帕米星）• Astromicin （阿司米星，福提霉素）• Spectinomycin （大观霉素）， etc.

Aminoglycosides Aminoglycosides agents

1. 1. ADMEADMEi) Ai) Absorption:bsorption: IMIM

ii) Dii) Distribution: mainly at extracellular fluistribution: mainly at extracellular fluid, crosses the BBB and achieves theraid, crosses the BBB and achieves therapeutic concentrations with inflamed mepeutic concentrations with inflamed menings.nings.

iii) Eiii) Excretion:xcretion: 90%, kidney90%, kidney

ageage↑↑→→ T T1/21/2↑↑

StreptomycinStreptomycin

2.Clinical uses2.Clinical uses

i) plague(i) plague( 鼠疫鼠疫 ) and tularemia() and tularemia( 兔热病兔热病 ): ): ccombination with an oral tetracycline.ombination with an oral tetracycline.

ii) tuberculosis: ii) tuberculosis: as first-line agentas first-line agentiii) bacterial endocarditis: iii) bacterial endocarditis: ((enterococcalenterococcal肠球菌肠球菌 , , viridans streptococcalviridans streptococcal 草绿色链草绿色链球菌球菌 , , etc.etc.), ), streptomycin and penicillin streptomycin and penicillin produce a synergistic bactericidal.produce a synergistic bactericidal.


3. Adverse reactions3. Adverse reactions

i) i) Allergic reactionAllergic reaction skin rashes, fever, skin rashes, fever, anaphylactic shockanaphylactic shockii) ii) Ototoxicity (Ototoxicity (cochlea > vestibular orgacochlea > vestibular orga

nn))iii) iii) Neuromuscular blockade (paralysis)Neuromuscular blockade (paralysis)iv) iv) NephrotoxicityNephrotoxicity


1. 1. ADME ADME Gentamicin can accumulate in cortex Gentamicin can accumulate in cortex

of the kidney .of the kidney .2.Clinical use : 2.Clinical use : ii) important agent (first choice) for seriii) important agent (first choice) for seri

ous Gous G-- bacillary infections (sepsis, pn bacillary infections (sepsis, pneumonia, eumonia, etcetc.), because of its low cost .), because of its low cost and reliable activity.and reliable activity.

GentamicinGentamicin

2.Clinical Uses : 2.Clinical Uses :

ii) infection induced by ii) infection induced by enterococcalenterococcal, , viriviridans streptococcaldans streptococcal, , staphylococcal etc. staphylococcal etc. GGentamicin is used concurrently with oentamicin is used concurrently with other antibiotics (e.g. ther antibiotics (e.g. -lactams) -lactams)

iii) prevent the infection induced by operiii) prevent the infection induced by operationation


2.Clinical Uses : 2.Clinical Uses :

iv) local application: for treatment of iv) local application: for treatment of infected burn, wounds,or skin infected burn, wounds,or skin lesions and the prevention of lesions and the prevention of intravenous catheter infections, intravenous catheter infections, etc.etc.



i) i) Ototoxicity (Ototoxicity (vestibular organvestibular organ > cochlea> cochlea))

ii) ii) NephrotoxicityNephrotoxicity

iii) Nausea and vomitingiii) Nausea and vomiting etc etc..


1.1. antimicrobial activity & pharmacokineantimicrobial activity & pharmacokineticstics: very : very similar to those of getamicin.similar to those of getamicin.

2. Adverse reactions: 2. Adverse reactions: Ototoxicity and NeOtotoxicity and Nephrotoxicity (may be less than dose gphrotoxicity (may be less than dose gentamicin).entamicin).

TobramycinTobramycin

1.Antibacterial activity:1.Antibacterial activity:

The The spectrumspectrum of antimicrobial activit of antimicrobial activity of amikacin is they of amikacin is the broadest broadest in the in the group.group.

AmikacinAmikacin

2.Clinical uses : 2.Clinical uses : • Treatment of G-bacillary infections which Treatment of G-bacillary infections which

resistance to gentamicin and tobramycin. resistance to gentamicin and tobramycin. • Most strains resistance to amikacin founMost strains resistance to amikacin foun

d is also resistance to other aminoglycod is also resistance to other aminoglycosides. sides.

• combination with combination with -lactams, produce a s-lactams, produce a synergistic bactericidal.ynergistic bactericidal.

AmikacinAmikacin


i) i) Ototoxicity (Ototoxicity (cochleacochlea > vestibular organ> vestibular organ))

ii) ii) Nephrotoxicity Nephrotoxicity (may be less than gentami(may be less than gentamicin or Tobramycin).cin or Tobramycin).

iii) iii) Neuromuscular blockade (paralysis)Neuromuscular blockade (paralysis) ，， rarrarelyely

iv) skin rashes, fever, nausea and vomitingiv) skin rashes, fever, nausea and vomiting et etcc..

AmikacinAmikacin

i) similar to gentamicin & tobramycin ii) similar to gentamicin & tobramycin in its pharmacokinetic properties.n its pharmacokinetic properties.

ii) broad spectrum, against aerobic G- ii) broad spectrum, against aerobic G- bacilli. bacilli.

iii) tolerance to many aminoglycosidesiii) tolerance to many aminoglycosides - inactivating enzymes. - inactivating enzymes.

iv) less toxiciv) less toxic

NetilmicinNetilmicin

Part BPart B Polymyxins Polymyxins

1. 1. Polymyxin Polymyxin A,A,B,B,C,D,C,D,EE2.2.Notice: Notice: because of the extreme toxicity, because of the extreme toxicity,

they are now rarely used. they are now rarely used.

3. 3. Antibacterial activity:Antibacterial activity: they are restricte they are restricted to G- bacilli (d to G- bacilli (NarrowNarrow spectrum)spectrum)

4.Mechanism of action: 4.Mechanism of action: they interact with they interact with phospholipids and penetrate into and dphospholipids and penetrate into and disrupt the structure of cell membranes.isrupt the structure of cell membranes.

Lipopoly-saccharide

Outermembrane

Peptidoglycan

Cytoplasmicmembrane

polymyxinspolymyxins


4. Clinical uses: 4. Clinical uses: infection of Pseudomonainfection of Pseudomonas aeruginosa (s aeruginosa ( 铜绿假单胞菌属铜绿假单胞菌属 ) and oth) and other G- bacilli, local application.er G- bacilli, local application.

Resisitance rarely happened.Resisitance rarely happened.


5. Adverse reaction(25%):5. Adverse reaction(25%):

i) i) Nephrotoxicity (22.2%)Nephrotoxicity (22.2%)

ii) Neurotoxicity: ii) Neurotoxicity: NeuromusNeuromuscular blockade (paralysis)cular blockade (paralysis)

iii) Allergic reactioniii) Allergic reaction

iv) others: hepatotoxicityiv) others: hepatotoxicity

Tetracyclines & Chloramphenicoletracyclines & Chloramphenicol

Section 5Section 5

Part APart A Tetracyclinesetracyclines

Two classes: Two classes: • crude productcrude product

Tetracycline(Tetracycline( 四环素四环素 ))

Cholortetracycline (Cholortetracycline ( 金霉素金霉素 ))

Oxytetracycline (Oxytetracycline ( 土霉素土霉素 ))• semisynthetic derivativesemisynthetic derivative

Doxycycline(Doxycycline( 多西环素多西环素 ))

Minocycline(Minocycline( 米诺环素米诺环素 ))

Part APart A Tetracyclinesetracyclines

Antimicrobial activity:Antimicrobial activity:

• bacteriostatic bacteriostatic

• bactericidal (high concentration)bactericidal (high concentration)

• Minocycline > Doxycycline > TetracyclineMinocycline > Doxycycline > Tetracycline

General properties of TetracyclinesGeneral properties of Tetracyclines

““broad-spectrumbroad-spectrum” antibiotic” antibiotic

• Rickattsiae Rickattsiae ((立克次体立克次体 ))• a number of a number of aerobic and anaerobic aerobic and anaerobic GG++

& G& G-- bacteria bacteria • Chlamydia Chlamydia ((衣原体衣原体 ))• Coxiella burnetii Coxiella burnetii ((螺旋体螺旋体 ))• Mycoplasma pneumoniae Mycoplasma pneumoniae ((支原体支原体 ) ) • PlasmodiumPlasmodium ((疟原虫疟原虫 ))• not active against fungi, virus.not active against fungi, virus.


Mechanism of action:Mechanism of action: Bind to 30S subunit of ribosome,

preventing access of aminoacyl tRNA to acceptor (A) site on the mRNA-ribosome complex


Resistance Resistance Mechanism:Mechanism:

(1) Decreased intracellular (1) Decreased intracellular accumulation due to either impaired accumulation due to either impaired influx or increased efflux by a active influx or increased efflux by a active transport protein pump.transport protein pump.

(2) Ribosome protection that interfere (2) Ribosome protection that interfere with the tetracycline binding to the with the tetracycline binding to the ribosome.ribosome.

(3) Enzyme inactivation of tetracycline.(3) Enzyme inactivation of tetracycline.


ADADME :ME :

(1) (1) AAbsorption are impaired by food (except doxycycline bsorption are impaired by food (except doxycycline and minocycline).and minocycline).

(2) (2) DDistributed widely to tissue and body fluid except for istributed widely to tissue and body fluid except for CSF.CSF.

• across the placenta and are also excreted in the milk.across the placenta and are also excreted in the milk.

• tetracyclines are bound to- and damage- growing bontetracyclines are bound to- and damage- growing bones and teeth (chelation with calcium).es and teeth (chelation with calcium).

(3) (3) EExcreted mainly in bile and urine.xcreted mainly in bile and urine.



(1) Rickettsial((1) Rickettsial( 立克次体立克次体 ) infections.) infections.

(2) Mycoplasma((2) Mycoplasma( 支原体支原体 ) infections.) infections.

(3) Chlamydia((3) Chlamydia( 衣原体衣原体 ) infection.) infection.

(4) Leptospira((4) Leptospira( 螺旋体螺旋体 ) infection.) infection.

(5) Bacterial infection.(5) Bacterial infection.



(1) Gastrointestinal effects. (1) Gastrointestinal effects.

(2) Superinfections.(2) Superinfections.

(3) Deposition of the drugs in growing teeth and bo(3) Deposition of the drugs in growing teeth and bo

nes.nes.

(4) Hepatic toxicity and renal toxicity.(4) Hepatic toxicity and renal toxicity.

(5) Photosensitivity.(5) Photosensitivity.

(6) Vestibular toxicity ((6) Vestibular toxicity (minocycline).minocycline).


Brown discoloration of teeth due to tetracycline exposure.

• Tetracycline (Tetracycline ( 四环素四环素 ))

• Doxycycline (Doxycycline ( 多西环素多西环素 ))

• Minocycline (Minocycline ( 米诺环素米诺环素 ))

TetracyclinesTetracyclines agentsagents

Part BPart B Chloramphenicol Chloramphenicol

p 1246 p 1246

p776pharm p776pharm

Chemical structureChemical structure


(1) a wide antimicrobial spectrum.(1) a wide antimicrobial spectrum.

(2) primarily bacteriostatic , may be b(2) primarily bacteriostatic , may be bactericidal to certain species.actericidal to certain species.

ChloramphenicolChloramphenicol

2. Mechanism of action2. Mechanism of action

Acts primarily by binding reversibly to Acts primarily by binding reversibly to

the 50 S ribosomal subunit (near the sthe 50 S ribosomal subunit (near the s

ite of action of macrolides and clindaite of action of macrolides and clinda

mycin, which it inhibits competitively).mycin, which it inhibits competitively).


2. Mechanism of Resistance2. Mechanism of Resistance

(1) a plasmid-encoded acetyltransfer(1) a plasmid-encoded acetyltransferase that inactives the drugsase that inactives the drugs

(2) low permeability of bacterial cell (2) low permeability of bacterial cell membranemembrane



(1)Hematological Toxicity: (1)Hematological Toxicity: • dose-related toxic effect dose-related toxic effect anemia, leukopenia, thrombocytopenia anemia, leukopenia, thrombocytopenia • idiosyncratic responseidiosyncratic response aplastic anemia(aplastic anemia(再障再障 ), fatal pancytopenia. ), fatal pancytopenia. (2) Gray baby syndrome.(2) Gray baby syndrome.(3) hypersensitivty reaction, etc.(3) hypersensitivty reaction, etc.

4. Drugs interactions 4. Drugs interactions inhibits Cy P450 enzyme mediated metabolism inhibits Cy P450 enzyme mediated metabolism

of warfarin, phenytoin, etc.of warfarin, phenytoin, etc.


5.Clinical uses5.Clinical uses

(1) Bacterial meningitis.(1) Bacterial meningitis.

(2) Typhoid fever((2) Typhoid fever( 伤寒伤寒 ) and other types of ) and other types of

systemic systemic Salmonella Salmonella infections. infections.

(3) Eye bacterial infection. (3) Eye bacterial infection.

(4) Anaerobic infection.(4) Anaerobic infection.

(5) Rickettsial disease and brucellosis, (5) Rickettsial disease and brucellosis, etc.etc.


Thanks !

macrolides, lincomycins &vancomycins section 3 yun-bi lu, phd 卢韵碧 dept. of pharmacology,...

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