T etracyclines & Chloramphenicol

Tetracyclines & Chloramphenicoletracyclines & Chloramphenicol

Chapter 42Chapter 42

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

2013.12.26

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



Mechanism of action:Mechanism of action:

①①ChloramphenicolChloramphenicol

②②Macrolides, ClindMacrolides, Clindamycinamycin

③③TetracyclinesTetracyclines

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 influx or increased efflux by a active active transport protein pumptransport protein pump..

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

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


Clinical UsesClinical Uses

(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.


Adverse reactionsAdverse reactions

(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 (( 氯霉氯霉素素 ))

p 1246 p 1246

p776pharm p776pharm

Chemical structureChemical structure

1. 1. Antimicrobial activity:Antimicrobial activity:

(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).


Mechanism of action:Mechanism of action:

①①ChloramphenicolChloramphenicol

②②Macrolides, ClindMacrolides, Clindamycinamycin

③③TetracyclinesTetracyclines

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


3.Clinical uses3.Clinical uses

(1) Bacterial meningitis(1) Bacterial meningitis ，， brain abscess.brain abscess.

(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.


4. Adverse reactions4. Adverse reactions

(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( 全血细全血细

胞减少症胞减少症 ). ). (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 of inhibits Cy P450 enzyme mediated metabolism of

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


SyntheticSynthetic antimicrobial agents antimicrobial agents

Chapter 43Chapter 43

• Quinolones ( Quinolones ( 喹诺酮类喹诺酮类 ))

• Sulfonamides ( Sulfonamides ( 磺胺类磺胺类 ))

• Other Synthetic antimicrobialOther Synthetic antimicrobial Trimethoprim (Trimethoprim ( 甲氧苄啶甲氧苄啶 ))

Nitrofurans (Nitrofurans ( 硝基呋喃类硝基呋喃类 ))

ContentsContents

From chloroquine to nalidixic acidFrom chloroquine to nalidixic acid

Generation Example timeGeneration Example time

1 Nalidixic acid 1 Nalidixic acid 萘啶酸萘啶酸 19621962

2 Pipemidic acid 2 Pipemidic acid 吡哌酸吡哌酸 19731973

3 3 NorfloxacinNorfloxacin 诺诺氟氟沙星沙星 19801980

4 Clinfloxacin 4 Clinfloxacin 克林沙星克林沙星 1990’s1990’s

喹诺酮类喹诺酮类 (Quinolones)(Quinolones)

First generation fluoroquinolonesFirst generation fluoroquinolones

( 诺氟沙星 ) ( 环丙沙星 )

( 氧氟沙星 )( 培氟沙星 )

From ofloxacin to levofloxacinFrom ofloxacin to levofloxacin

Fluoroquinolones

• broad antimicrobial activity broad antimicrobial activity

• effective after oral administration effective after oral administration

• relatively few side effects relatively few side effects

• resistance to their action does not resistance to their action does not develop rapidly. develop rapidly.

FluoroquinolonesFluoroquinolones

1. Antimicrobial activity & spectrum: 1. Antimicrobial activity & spectrum:

(1) bactericidal and have significant PAE. (1) bactericidal and have significant PAE.

(2) aerobic G(2) aerobic G-- bacteria, bacteria, PseudomonasPseudomonas, , aeroaerobic Gbic G++ bacteria, bacteria, ChlamydiaChlamydia spp. spp. （衣原（衣原体）体） , Legionella pneumophila(, Legionella pneumophila( 军团菌军团菌 ) , a) , anaerobic bacteria, mycobacteria(naerobic bacteria, mycobacteria( 分枝杆分枝杆菌菌 ), multiple-resistance strains.), multiple-resistance strains.

General properties of General properties of QuinolonesQuinolones

Mechanism of actionMechanism of action

Topoisomerase Topoisomerase

DNA gyrase DNA gyrase

Key enzymes in DNA replication: bacterial DNA is supercoiled.Key enzymes in DNA replication: bacterial DNA is supercoiled.


Topo Topo isomeraseisomeraseDNA gyraseDNA gyrase

Gram (-)Gram (-) Gram (+)Gram (+)

porinporin


Fluoroquinolones:Fluoroquinolones:4 stacked molecules4 stacked molecules

DNA gyraseDNA gyraseCatalytic subuniteCatalytic subunite

DNA gyraseDNA gyraseATP binding subuniteATP binding subunite

Mechanism of resistanceMechanism of resistance

Topo Topo isomeraseisomeraseDNA gyraseDNA gyrase

Gram (-)Gram (-) Gram (+)Gram (+)

porinporin

mutation of mutation of the enzymesthe enzymes

active effluxactive effluxsystemsystem

decreaseddecreasedpermeabilitypermeability

• AAbsorption: well absorbed; bound by divalent cationsbsorption: well absorbed; bound by divalent cations– Do not administer with iron, magnesium, calciumDo not administer with iron, magnesium, calcium

• DDistribution: all distribute widely (istribution: all distribute widely (even in CSF)even in CSF), and , and most concentrate in urinemost concentrate in urine

• MMetabolism: etabolism: – hepatic metabolism diminishes the activity of norfloxacin hepatic metabolism diminishes the activity of norfloxacin

and ciprofloxacinand ciprofloxacin– Several have predominately hepatic clearanceSeveral have predominately hepatic clearance

(Grepafloxacin(Grepafloxacin格雷沙星格雷沙星 , Sparfloxacin, Trovafloxacin, Sparfloxacin, Trovafloxacin曲伐沙星曲伐沙星 ) )

• EExcretion: urinary excretion predominates for the first xcretion: urinary excretion predominates for the first generation generation fluoroquinolonesfluoroquinolones

ADME of fluoroquinolonesADME of fluoroquinolones

ADME of fluoroquinolonesADME of fluoroquinolones

• Urinary tract infections.Urinary tract infections.

• GI and abdominal infections.GI and abdominal infections.

• Respiratory tract infections.Respiratory tract infections.

• Bone, joint and soft tissues infections, Bone, joint and soft tissues infections, OsteomyelitisOsteomyelitis..

• MeningitisMeningitis

• STD: STD: Neisseria gonorrheaNeisseria gonorrhea ( ( 奈瑟氏淋球奈瑟氏淋球菌菌 ))and and ChlamydiaChlamydia ( ( 衣原体衣原体，， Quinolone Quinolone resistance in resistance in gonorrheagonorrhea increasing) increasing)

Clinical UsesClinical Uses

•Gastrointestinal effects. Gastrointestinal effects.

•CNS side effects.CNS side effects.

•Allergic reaction.Allergic reaction.

•Hepatotoxicity, nephrotoxicity. Hepatotoxicity, nephrotoxicity.

•Joint/cartilage toxicity, TendinopathyJoint/cartilage toxicity, Tendinopathy

–Achilles tendon rupture ( 跟腱断裂 )

–Limited FDA approval for children

Adverse reactionsAdverse reactions

• NorfloxacinNorfloxacin (( 诺氟沙星诺氟沙星 ))• Ciprofloxacin Ciprofloxacin (( 环丙沙星环丙沙星 ))• Ofloxacin Ofloxacin (( 氧氟沙星氧氟沙星 ))• Levofloxacin Levofloxacin (( 左氧氟沙星左氧氟沙星 ))• LomefloxacinLomefloxacin (( 洛美沙星洛美沙星 ))• Fleroxacin Fleroxacin (( 氟罗沙星氟罗沙星 ))• Sparfloxacin Sparfloxacin (( 司帕沙星司帕沙星 ))• Clinafloxacin (Clinafloxacin ( 克林沙星克林沙星 ))• Gatifloxacin (Gatifloxacin ( 加替沙星加替沙星 ))

Fluoroquinolones agentsFluoroquinolones agents

• Quinolones ( Quinolones ( 喹诺酮类喹诺酮类 ))

• Sulfonamides ( Sulfonamides ( 磺胺类磺胺类 ))

• Other Synthetic antimicrobialOther Synthetic antimicrobial Trimethoprim (Trimethoprim ( 甲氧苄啶甲氧苄啶 ))

Nitrofurans (Nitrofurans ( 硝基呋喃类硝基呋喃类 ))

ContentsContents

Inhibitors of Folate Synthesis

2,4-Diaminoazobenzen-4’-sulfonamide

Prontosil ( 百浪多息 )

Gerhard DomagkNobel Laureate 1939

First Aid Packet carried by U.S. Soldiers in World War II

http://home.att.net/~steinert/wwii.htm

Sulfonamides (Sulfonamides ( 磺胺类磺胺类 ))

Antimicrobial activity:Antimicrobial activity:• A wide antimicrobial spectrum.A wide antimicrobial spectrum.• Exerting onlyExerting only bacteriostatic effect.bacteriostatic effect.

对 - 氨基苯甲酸


Pteridine+PABA

Blocked by sulfonamides

Dihydropteroic acid

Dihydrofolic acid

glutamate

Tetrahydrofolic acid

Blocked by trimethoprim

NADPH

NADP+

Dihydropteroatesynthase

Dihydrofolatereductasease

蝶啶

二氢蝶酸合成酶

二氢叶酸还原酶

Mechanism of ResistanceMechanism of Resistance • A lower affinityA lower affinity for sulfonamides by the dih for sulfonamides by the dih

ydropteroate synthaseydropteroate synthase• Decreased cell permeabilityDecreased cell permeability or active efflux or active efflux

of the drugof the drug• An alternative pathwayAn alternative pathway to synthesis the es to synthesis the es

sential metabolitessential metabolites• An increased productionAn increased production of essential meta of essential meta

bolitesbolites

ADME of sulfonamidesADME of sulfonamides

• AApproximately 70%-100% of an oral dose is approximately 70%-100% of an oral dose is absorbed.bsorbed.

• DDistributing throughout all tissues of the bodistributing throughout all tissues of the body,y, even ineven in CSF CSF ( sulfadiazine ( sulfadiazine 磺胺嘧啶磺胺嘧啶 and sand sulfamethoxazole ulfamethoxazole 磺胺甲噁唑磺胺甲噁唑 , may be effectiv, may be effective in meningeal infections) ;readily passing the in meningeal infections) ;readily passing though ough the placentathe placenta..

• MMetabolized etabolized in the liverin the liver by acetylation. by acetylation.

ADME of sulfonamidesADME of sulfonamides

• EEliminated mainly liminated mainly in the urinein the urine as the as the unchanged drug and metabolic unchanged drug and metabolic product. In acid urine, the eliminated product. In acid urine, the eliminated may precipitate, thus induced may precipitate, thus induced renal renal disturbance. disturbance.

Clinical usesClinical uses

• Systemic infections.Systemic infections.

• Intestinal Intestinal infections.infections.

• Infections of burn and wound.Infections of burn and wound.

Adverse reactionsAdverse reactions• Urinary tract disturbancesUrinary tract disturbances• Hypersensitivity reactionHypersensitivity reaction• Hematopoietic system disturbancesHematopoietic system disturbances• Kernicterus (Kernicterus ( 胆红素脑病胆红素脑病 ))• HepatitisHepatitis• GI effectsGI effects

Drugs interactionsDrugs interactions• All sulfonamides are bound in varying deAll sulfonamides are bound in varying de

gree to gree to plasma protein.plasma protein.

Classification:Classification:

• Oral absorbable agentsOral absorbable agents• Short-acting agentsShort-acting agents• Medium-acting agentsMedium-acting agents• Long-acting agentsLong-acting agents• Oral nonabsorbable agents Oral nonabsorbable agents • Topical agentsTopical agents• Combination agentsCombination agents

Oral absorbable agentsOral absorbable agents

• Short-acting agentsShort-acting agents

Sulfafurazole Sulfafurazole (SIZ,(SIZ, 菌得清菌得清 ))• Medium-acting agentsMedium-acting agents

Sulfadiazine Sulfadiazine (SD,(SD, 磺胺嘧啶磺胺嘧啶 ))

Sulfamethoxazole Sulfamethoxazole (( 磺胺甲磺胺甲噁噁唑唑 , SMZ, , SMZ, 新诺明新诺明 ))• Long-acting agentsLong-acting agents

Sulfadoxine Sulfadoxine (( 磺胺多辛磺胺多辛 , SDM, SDM ，周效磺胺，周效磺胺 ))

Oral nonabsorbable agentsOral nonabsorbable agents

Sulfasalazine Sulfasalazine (( 柳氮磺吡啶柳氮磺吡啶 ) )

Topical agents.Topical agents.

Mafenide Mafenide (SML, (SML, 甲磺灭脓甲磺灭脓 ))

Sulfadiazine sliver Sulfadiazine sliver (( 磺胺嘧啶银磺胺嘧啶银 ))

Sulfacetamide Sulfacetamide (SA,(SA, 磺胺醋酰）磺胺醋酰）

Combination agents Combination agents Co-trimoxazole Co-trimoxazole (( 复方新诺明复方新诺明 ))

1) Features 1) Features • TrimethoprimTrimethoprim(( 甲氧苄啶甲氧苄啶 )) in combination in combination

with Sulfamethoxazole(1:5) exertswith Sulfamethoxazole(1:5) exerts a a synesynergistic effectsrgistic effects. .

• The ADME of the two agents is similar.The ADME of the two agents is similar.• Co-block essential enzymes ofCo-block essential enzymes of folate mefolate me

tabolism. tabolism.

Pteridine+PABA

Blocked by sulfonamides

Dihydropteroic acid

Dihydrofolic acid

glutamate

Tetrahydrofolic acid

Blocked by trimethoprim

NADPH

NADP+

Dihydropteroatesynthase

Dihydrofolatereductasease

2)Clinical Uses 2)Clinical Uses

• Chronic and recurrent infections in the urinChronic and recurrent infections in the urinary tractary tract

• Bacterial respiratory infectionsBacterial respiratory infections• GI infections (e.g. induced by GI infections (e.g. induced by SalmonellaSalmonella))• pneumocystis carinii pneumocystis carinii pneumoniapneumonia ( ( 肺囊虫性肺囊虫性

肺炎肺炎 ))

3)Adverse reactions

• There is no evidence that co-trimoxazole, when given in recommended dose, induced folate deficiency in normal persons.

• Hypersensitive reactions• GI effects• The effects of HIV patients• Drug interactions: warfarin, phenytoin

• Trimethoprim Trimethoprim (( 甲氧苄啶甲氧苄啶 ))

• Nitrofurans Nitrofurans (( 硝基呋喃类硝基呋喃类 ))

NitrofurantoinNitrofurantoin(( 呋喃妥因呋喃妥因 ))

Other Other SyntheticSynthetic antimicrobial antimicrobial

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T etracyclines & Chloramphenicol

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