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Part6 Part6 Synthetic antimicrobial agen Synthetic antimicrobial agen ts ts ( ( 人人人人人人人 人人人人人人人 ) ) Huifang Tang [email protected]

Part6 Synthetic antimicrobial agents ( 人工合成抗菌药 )

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Part6 Synthetic antimicrobial agents ( 人工合成抗菌药 ). Huifang Tang [email protected]. Classification of Synthetic antimicrobial agents. Ⅰ. Quinolones( 喹诺酮类 ); Ⅱ. Sulfonamides( 磺胺类 ); Ⅲ. Other synthetic antimicrobial agents: Trimethoprim ( 甲氧苄啶 ) Nitrofurans ( 硝基呋喃类 ), etc. - PowerPoint PPT Presentation

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Page 1: Part6 Synthetic antimicrobial agents ( 人工合成抗菌药 )

Part6Part6 Synthetic antimicrobial agentsSynthetic antimicrobial agents(( 人工合成抗菌药人工合成抗菌药 ))

Huifang Tang [email protected]

Page 2: Part6 Synthetic antimicrobial agents ( 人工合成抗菌药 )

Classification of Synthetic antimicrobial agents

• Ⅰ. Quinolones( 喹诺酮类 );• Ⅱ. Sulfonamides( 磺胺类 );• Ⅲ. Other synthetic antimicrobial agents:• Trimethoprim ( 甲氧苄啶 )• Nitrofurans ( 硝基呋喃类 ), etc.

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General features• Broad antimicrobial activity and are

effective after oral administration for the treatment of a wide variety of infectious disease.

• Relatively few side effects.• Microbial resistance to their action

does not develop rapidly.

Quinolones

Quinolones

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Chemistry

•Derived from basic structure of nalidixic acid ( 萘啶酸 )and have substituents at N-1, C-5, C-7, position 8 and a fluorine atom at position 6. •Fluorine at position 6 enhances gyrase inhibition and cell penetration.

QuinolonesQuinolonesQuinolones

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Chemical structure

Quinolones

(( 诺氟沙星诺氟沙星))

(( 环丙沙星环丙沙星))

(( 萘啶酸萘啶酸 ))

Quinolones

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Generation Examples1 st (1962-1969) Nalidixic acid, 萘啶酸2 nd (1969-1979) Pipemidic acid 吡哌酸

Cinoxacin 西诺沙星3 rd (1980-1996) Norfloxacin 诺氟沙星

Levofloxacin 左氧氟沙星 Ciprofloxacin 环丙沙星

Ofloxacin 氧氟沙星sparfloxacin 司帕沙星

4 th (1997-) Grepafloxacin 格帕沙星Clinafloxacin 克林沙星Gatifloxacin 加替沙星Moxifloxacin 莫西沙星

ClassificationQuinolones

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First-generation agents(1962-1969) First-generation agents(1962-1969)

Nalidixic acid, Nalidixic acid, 萘啶酸萘啶酸•The first generation drug of the quinolone antiThe first generation drug of the quinolone antibioticsbiotics •Moderate gram-negative activity and minimal Moderate gram-negative activity and minimal systemic distributionsystemic distributionClinical applications Clinical applications • Uncomplicated urinary tract infectionsUncomplicated urinary tract infections

QuinolonesQuinolonesQuinolones

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Second-generation quinolones Second-generation quinolones (1969-197(1969-1979)9)

Pipemidic acid Pipemidic acid 吡哌酸吡哌酸 CinoxacinCinoxacin 西诺沙星西诺沙星

•Expanded gram-negative activity and atypical Expanded gram-negative activity and atypical pathogen coverage, but limited gram-positive apathogen coverage, but limited gram-positive activity. ctivity. •Most active against aerobic gram-negative bacMost active against aerobic gram-negative bacilliilli•Ciprofloxacin remains the quinolone most actiCiprofloxacin remains the quinolone most active against Pseudomonas aeruginosave against Pseudomonas aeruginosa

QuinolonesQuinolonesQuinolones

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Second-generation quinolones Second-generation quinolones (1969-197(1969-1979)9)

•Active against gram-positive and gram-negatiActive against gram-positive and gram-negative bacteria, mycobacteria, mycoplasmave bacteria, mycobacteria, mycoplasma 支原体支原体and legionella speciesand legionella species 军团杆菌属军团杆菌属 . . •Longer half-lives due to slow elimination, distrLonger half-lives due to slow elimination, distribution into many tissues and body fluids and pibution into many tissues and body fluids and penetration into human cells. enetration into human cells.

QuinolonesQuinolonesQuinolones

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Third-generation quinolones Third-generation quinolones (1980-199(1980-1996)6) Norfloxacin Norfloxacin 诺氟沙星诺氟沙星,, Levofloxacin Levofloxacin 左氧氟沙星左氧氟沙星,, Ciprofloxacin Ciprofloxacin 环丙沙星环丙沙星,, Ofloxacin Ofloxacin 氧氟沙星氧氟沙星,, Sparfloxacin Sparfloxacin 司帕沙星司帕沙星•Added potency against gram-negative bacterAdded potency against gram-negative bacteria, anaerobes and mycobacteria. ia, anaerobes and mycobacteria. •Retain expanded gram-negative and atypical Retain expanded gram-negative and atypical intracellular activity but have improved gram-intracellular activity but have improved gram-positive coveragepositive coverage

QuinolonesQuinolonesQuinolones

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Fourth-generation agents Fourth-generation agents (1997- )(1997- ) Grepafloxacin Grepafloxacin 格帕沙星,格帕沙星, Clinafloxacin Clinafloxacin 克林沙星,克林沙星,Gatifloxacin Gatifloxacin 加替沙星,加替沙星, Moxifloxacin Moxifloxacin 莫西沙星莫西沙星•Improve gram-positive coverage, maintain graImprove gram-positive coverage, maintain gram-negative coverage, and gain anaerobic coveram-negative coverage, and gain anaerobic coverage.ge.

QuinolonesQuinolonesQuinolones

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Antimicrobial activity & spectrumAntimicrobial activity & spectrum(1) Bactericidal and have significant PAE. (1) Bactericidal and have significant PAE. (2)Excellent activity against aerobic gram-ne(2)Excellent activity against aerobic gram-ne

gative bacteria, some agents have activity gative bacteria, some agents have activity against Pesudomonas. against Pesudomonas.

(3) Several newer agents with improved activ(3) Several newer agents with improved activity against aerobic gram-positive bacteria.ity against aerobic gram-positive bacteria.

QuinolonesQuinolonesQuinolones

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Antimicrobial activity & spectrumAntimicrobial activity & spectrum(4) They also are effective against Chlamydia s(4) They also are effective against Chlamydia s

pp.pp. (衣原体)(衣原体) , Legionella pneumophila(, Legionella pneumophila( 军军团菌团菌 ) ,anaerobic bacteria, mycobacteria() ,anaerobic bacteria, mycobacteria( 分分枝杆菌枝杆菌 ).).

(5) Some agents have limited activity against (5) Some agents have limited activity against multiple-resistance strains.multiple-resistance strains.

(( 66 )) Bactericidal concentration≥ bacteriostBactericidal concentration≥ bacteriostatic concentrationatic concentration

QuinolonesQuinolonesQuinolones

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Mechanism of actionsMechanism of actions Topoisomerases :Topoisomerases : enzymes that control and moenzymes that control and mo

dify the topological states of DNA in cells.dify the topological states of DNA in cells. • Topoisomerase ITopoisomerase I , , IIIIII catalyse merely the relcatalyse merely the rel

axation of DNAaxation of DNA• Topoisomerase II Topoisomerase II (( DNA gyraseDNA gyrase )) catalyse tcatalyse t

he supercoiling of DNAhe supercoiling of DNA• Topoisomerase IVTopoisomerase IV involved in the separation involved in the separation

process of the DNA daughter chains after chroprocess of the DNA daughter chains after chromosome duplication.mosome duplication.

QuinolonesQuinolonesQuinolones

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Mechanism of actions Mechanism of actions

The quinolone antibiotics target bacteriaThe quinolone antibiotics target bacterial l

• DNA gyrase (gram-negative bacteria) DNA gyrase (gram-negative bacteria) • Topoisomerase IV (gram- positive bactTopoisomerase IV (gram- positive bact

eria).eria).

QuinolonesQuinolonesQuinolones

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MechanismMechanism ofof actionaction

• Topoisomerase I,IIITopoisomerase I,III

• Topoisomerase II,IVTopoisomerase II,IV

Quinolones

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• The function of DNA gyrase is to introduce supercoils into the linThe function of DNA gyrase is to introduce supercoils into the linear DNA double helix, which results in the highly condensed 3-diear DNA double helix, which results in the highly condensed 3-dimensional structure of the DNA usually present inside the cell.mensional structure of the DNA usually present inside the cell.

• DNA gyrase consists of two proteins (A and B), with thDNA gyrase consists of two proteins (A and B), with the active species being a heterotetramer (A2B2).e active species being a heterotetramer (A2B2).

MechanismMechanism ofof actionactionQuinolones

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MechanismMechanism ofof actionactionQuinolones

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•The Gyr-A subunits were proposed to initially binThe Gyr-A subunits were proposed to initially bind to the double stranded DNA helix. d to the double stranded DNA helix. In an ATP-dependent process, described as "interIn an ATP-dependent process, described as "intermediate gate opening step", both DNA strands armediate gate opening step", both DNA strands are cleaved at certain 4 base pair staggered sites. e cleaved at certain 4 base pair staggered sites. •The 5'ends of the DNA chain are thereby bound cThe 5'ends of the DNA chain are thereby bound covalently to Tyrosin122 residues within the Gyr-A ovalently to Tyrosin122 residues within the Gyr-A subunits. subunits. •Gyr-B subunits are probably responsible for the Gyr-B subunits are probably responsible for the ATP-dependent resealing process of the DNA.ATP-dependent resealing process of the DNA.

MechanismMechanism ofof actionactionQuinolones

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•Topoisomerase IV : involved in the separation proceTopoisomerase IV : involved in the separation process of the DNA daughter chains after chromosome duplss of the DNA daughter chains after chromosome duplication.ication.•unable to catalyse the supercoiling of DNA, merely itunable to catalyse the supercoiling of DNA, merely its relaxation. s relaxation. •The enzyme comprises two subunits, ParC and ParE.The enzyme comprises two subunits, ParC and ParE.•The ParC protein is homologous to the gyrase A protThe ParC protein is homologous to the gyrase A protein, while the ParE subunit is homologous to the gyraein, while the ParE subunit is homologous to the gyrase B protein.se B protein.

MechanismMechanism ofof actionaction

Quinolones

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•Inhibition of topoisomerase IV → Inhibition of topoisomerase IV → interferes with seinterferes with separation of replicated chromosomal DNA into the reparation of replicated chromosomal DNA into the respective daughter cells during cell division.spective daughter cells during cell division.

•Inhibition of DNA gyrase →Inhibition of DNA gyrase →prevents the relaxation of prevents the relaxation of positively supercoiled DNA that is required for normal positively supercoiled DNA that is required for normal transcription and replicationtranscription and replication..

MechanismMechanism ofof actionactionQuinolones

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The enzyme binds two segments of DNA (1), creating a node of poThe enzyme binds two segments of DNA (1), creating a node of positive(+) superhelix. The enzyme then in-troduces a double-strand sitive(+) superhelix. The enzyme then in-troduces a double-strand break in the DNA and passes the front segment through the break (break in the DNA and passes the front segment through the break (2). The break is then resealed (3), creating a negative(-) supercoil.2). The break is then resealed (3), creating a negative(-) supercoil. QuinolonesQuinolones inhibit the nicking and closing activity of the gyrase, inhibit the nicking and closing activity of the gyrase, and also block the activity of toposomer-ase Ⅳ.and also block the activity of toposomer-ase Ⅳ.

Model of the formation of negtive DNA sModel of the formation of negtive DNA supercoils by DNA gyraseupercoils by DNA gyrase

11 22 33

(()) (-)(-)

Quinolones

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Mechanism of action

QuinolonesQuinolones inhibit the nicking and closiinhibit the nicking and closing activity of the gyraseng activity of the gyrase

Quinolones

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•Intrinsic resistance is rareIntrinsic resistance is rare•With a frequency of about one in 10With a frequency of about one in 1077–1–10099, especially among , especially among staphylococci, psestaphylococci, pseudomonas, and serratia(udomonas, and serratia( 沙雷氏菌沙雷氏菌 ).).

ResistanceResistance MechanismMechanism

Quinolones

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(1) Mutation of (1) Mutation of the gyrA genethe gyrA gene that encoded that encoded the A subunit polypeptide can confer resithe A subunit polypeptide can confer resistance to these drugs.stance to these drugs.

(2) Mutation of (2) Mutation of the gene cfxB and nfxBthe gene cfxB and nfxB that that encoded the porin decreased permeabilitencoded the porin decreased permeability of cell membrance. y of cell membrance.

(3) The high expression of (3) The high expression of norA genenorA gene (enco (encoded active pump protein) increased drugs ded active pump protein) increased drugs efflex by a active transport protein pump.efflex by a active transport protein pump.

(4) Plasmid mediated resistance.(4) Plasmid mediated resistance.

ResistanceResistance MechanismMechanismQuinolones

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(1) Well absorbed after oral admini(1) Well absorbed after oral administration.stration.

(2) Distributed widely in body tissu(2) Distributed widely in body tissue, even in CSF.e, even in CSF.

(3) Excreted mainly in urine. (3) Excreted mainly in urine. • Routes of elimination differ amonRoutes of elimination differ amon

g the Quinolones.g the Quinolones.

ADMEADME ofof QuinolonesQuinolonesQuinolones

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(1)(1)Urinary tract infections.Urinary tract infections.• The main indication for quinolones The main indication for quinolones • In the treatment of uncomplicated and cIn the treatment of uncomplicated and c

omplicated UTIs, cure rates can exceed 9omplicated UTIs, cure rates can exceed 90% and 80%, respectively.0% and 80%, respectively.

• Potent agents to use against HaemophiluPotent agents to use against Haemophilus ducreyi (s ducreyi ( 软性下疳嗜血杆菌软性下疳嗜血杆菌 ) and penicilli) and penicillin-sensitive and penicillin-resistant Neissn-sensitive and penicillin-resistant Neisseria gonorrhoeaeeria gonorrhoeae 淋淋 (( 病双病双 )) 球菌球菌 ..

ClinicalClinical UsesUsesQuinolones

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(2) GI and abdominal infections.(2) GI and abdominal infections.• Excellent in vitro activity against many enteExcellent in vitro activity against many ente

ric pathogens, including Escherichia coliric pathogens, including Escherichia coli 大大肠杆菌肠杆菌 , Aeromonas, Aeromonas 气单胞菌属气单胞菌属 , Shigella, Shigella 志贺( 氏 ) 杆菌 , Salmonella, Salmonella 沙门氏菌 , Campyloba, Campylobactercter 弯曲杆菌属 , Vibrio, Vibrio 弧菌属 , and Yersinia s, and Yersinia speciespecies 耶尔森菌耶尔森菌

• Furthermore, quinolone drug concentrationFurthermore, quinolone drug concentrations in feces are exceedingly high.s in feces are exceedingly high.

ClinicalClinical UsesUsesQuinolones

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(3) Respiratory tract infections.(3) Respiratory tract infections.• Have inferior activity against streptococciHave inferior activity against streptococci 链球菌链球菌 anan

d should not be used as primary therapy for commod should not be used as primary therapy for common upper respiratory tract infections. n upper respiratory tract infections.

• Alternatives for treatment of acute exacerbation of Alternatives for treatment of acute exacerbation of chronic bronchitis in patients with obstructive pulchronic bronchitis in patients with obstructive pulmonary disease who are intolerant of or have develmonary disease who are intolerant of or have developed resistance to first-line antibiotics.oped resistance to first-line antibiotics.

• antibiotics with activity against Streptococcus pneantibiotics with activity against Streptococcus pneumoniae, Haemophilus influenzaeumoniae, Haemophilus influenzae 流感流感 (( 嗜血嗜血 )) 杆菌杆菌 , , and Moraxella catarrhalisand Moraxella catarrhalis 粘膜炎莫拉菌粘膜炎莫拉菌 . .

(4) Other infections(4) Other infections :: Bone, joint anBone, joint and soft tissue infections.d soft tissue infections.

ClinicalClinical UsesUsesQuinolones

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(1)Gastrointestinal effects.(1)Gastrointestinal effects.• The most common reactions The most common reactions (2)CNS side effects.(2)CNS side effects.• Penetrate BBB→ GABA↓Penetrate BBB→ GABA↓(3)Allergic reaction.(3)Allergic reaction.• Skin rashses, itchs, angioneuroedema , etc.Skin rashses, itchs, angioneuroedema , etc.• PhotosensitivityPhotosensitivity(4)other effects.(4)other effects.• Cardiac toxicityCardiac toxicity : : Q-T interval↑Q-T interval↑• Liver and renal injuryLiver and renal injury

AdverseAdverse reactionsreactions

Quinolones

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(4)other effects.(4)other effects.• Muscle skeletal system Muscle skeletal system • Amyasthenia Amyasthenia 肌无力肌无力 , myosalgia, myosalgia肌痛肌痛 , joint pain and inflammation, joint pain and inflammation

• Increase intracranial pressure in iIncrease intracranial pressure in infantsnfants

AdverseAdverse reactionsreactions

Quinolones

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• Pipemidic acid (Pipemidic acid ( 吡哌酸吡哌酸 ))• Norfloxacin (Norfloxacin ( 诺氟沙星诺氟沙星 ))• Ciprofloxacin (Ciprofloxacin ( 环丙杀星环丙杀星 ))• OfloxacinOfloxacin (氧氟沙星)(氧氟沙星)• LevofloxacinLevofloxacin (左氧氟沙星)(左氧氟沙星)• LomefloxacinLomefloxacin (洛美沙星)(洛美沙星)• FleroxacinFleroxacin (氟罗沙星)(氟罗沙星)• SparfloxacinSparfloxacin (司帕沙星)(司帕沙星)

QuinolonesQuinolones agentsagents

Quinolones

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PharmacokineticPharmacokinetic PropertiesProperties ofof FluoroquinolonesFluoroquinolones

Quinolones

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盐酸安妥沙星-- 我国第一个具有自主知识产权的沙星类抗菌药 • 盐酸安妥沙星与细菌作用 2到 4小时,即可杀灭 99% 以上细菌。

• 在沙星类药物安全性的重要指标———光毒性方面,它的毒性明显低于现有主要产品洛美沙星、司帕沙星、氟罗沙星、环丙沙星。

• 盐酸安妥沙星具有优异的药物代谢性质,与最新的第四代沙星类药物相比,它的口服剂量最低,每天只需服用 1次,属长效抗菌药物。

• 盐酸安妥沙星治疗呼吸道、泌尿道、皮肤软组织等三大系统细菌感染性疾病,疗效确切而不良反应少,总有效率超过 95% 。

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喹诺酮类研究两大动向 • 继续研发第四代氟喹诺酮

– 近年上市的 : 吉米沙星 (gemifloxacin ), 巴洛沙星

– 目前正在研发中的 : 西他沙星 (sitafloxacin ),奥鲁沙星 (olamufloxacin ) 。

• 注意研究结构变幅更大的喹诺酮– 近年上市的帕珠沙星 (pazufloxacin ) 、鲁利沙星 (prulifloxacin )

– 非氟喹诺酮格林沙星 (garenoxacin )

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SulfonamidesSulfonamides

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SulfonamideSulfonamidess

Sulfonamides

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(1) (1) SulfonamidesSulfonamides have a wide range of have a wide range of antimicrobial activity.antimicrobial activity.

• G+,G- bacteria, Nocardia G+,G- bacteria, Nocardia 诺卡菌属诺卡菌属 , Beds, Bedsonia trachomatisonia trachomatis 沙眼衣原体沙眼衣原体 , etc., etc.

• Enteric bacteria etc. less effectiveEnteric bacteria etc. less effective• Rickett's organismRickett's organism

(2) (2) SulfonamidesSulfonamides exert only bacteriostatic exert only bacteriostatic effect.effect.

AntimicrobialAntimicrobial activityactivity

Sulfonamides

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• Structural analogs and compeStructural analogs and competitive antagonists of para-amititive antagonists of para-aminobenzoic acid (nobenzoic acid ( 对氨基苯甲酸 对氨基苯甲酸 PABA) PABA)

• Prevent normal bacterial utilizPrevent normal bacterial utilization of PABA for the synthesis ation of PABA for the synthesis of folic acid. of folic acid.

Mechanism of actionMechanism of action

Sulfonamides

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Mechanism of actionMechanism of action

Sulfonamides

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• Originate by random mutatioOriginate by random mutation and selection or by transfer n and selection or by transfer of resistance by plasmaides. of resistance by plasmaides.

• Such resistance usually is perSuch resistance usually is persistent and irreversible. sistent and irreversible.

Mechanism of ResistanceMechanism of Resistance

Sulfonamides

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The resistance characterized by:The resistance characterized by:(1)A lower affinity for sulfonamides by th(1)A lower affinity for sulfonamides by th

e dihydropteroate synthasee dihydropteroate synthase(2)Decreased cell permeability or active e(2)Decreased cell permeability or active e

fflux of the drugfflux of the drug(3)An alternative pathway to synthesis th(3)An alternative pathway to synthesis th

e essential metabolitese essential metabolites(4)An increased production of essential m(4)An increased production of essential m

etaboltesetaboltes

Mechanism of ResistanceMechanism of Resistance

Sulfonamides

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(1) Oral absorbable agents(1) Oral absorbable agents• Short-acting agentsShort-acting agents• Medium-acting agentsMedium-acting agents• Long-acting agentsLong-acting agents(2) Oral nonabsorbable agents (2) Oral nonabsorbable agents (3) Topical agents.(3) Topical agents.(4) Combination agents. (4) Combination agents.

ClassificationClassification

Sulfonamides

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(1)(1) systemic infections.systemic infections.• cerebral meningitis cerebral meningitis • Tympanitis Tympanitis 中耳炎中耳炎• Uncomplicated urinary tract infectionsUncomplicated urinary tract infections• Combined with TMP in treating complicated urinCombined with TMP in treating complicated urin

ary tract infections,respiratory infections,GI infecary tract infections,respiratory infections,GI infectionstions

(2) intestinal infections.(2) intestinal infections.• Sulfasalazine Sulfasalazine 柳氮磺吡啶柳氮磺吡啶(3) infections of burn and wound.(3) infections of burn and wound.• Sulfadiazine sliver(Sulfadiazine sliver( 磺胺嘧啶银磺胺嘧啶银 ))

ClinicalClinical usesuses

Sulfonamides

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(1)Urinary tract disturbances(1)Urinary tract disturbances(2)Hypersensitivity reaction(2)Hypersensitivity reaction(3)Hematopoietic system disturbances↓(3)Hematopoietic system disturbances↓(4)Kernicterus (4)Kernicterus 脑核黄疸脑核黄疸• caused by bilirubincaused by bilirubin 胆红素 胆红素 replacementreplacement(5)Hepatitis(5)Hepatitis(6)GI disturbances(6)GI disturbances

Adverse reactionsAdverse reactions

Sulfonamides

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(1) Approximately 70%-100% of an oral dose i(1) Approximately 70%-100% of an oral dose is absorbed.s absorbed.

(2) Sulfonamides are distributed throughout (2) Sulfonamides are distributed throughout all tissues of the body, even in CSF all tissues of the body, even in CSF

• SulfadiazineSulfadiazine 磺胺嘧啶磺胺嘧啶 and sulfisoxazoleand sulfisoxazole 磺胺磺胺异恶唑异恶唑 , may be effective in meningeal infect, may be effective in meningeal infections .ions .

(3) Sulfonamides readily pass though the plac(3) Sulfonamides readily pass though the placenta.enta.

ADME of sulfonamidesADME of sulfonamides

Sulfonamides

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(4) Sulfonamides are metabolized in (4) Sulfonamides are metabolized in the liver by acetylation. the liver by acetylation.

(5) Sulfonamides eliminated mainly i(5) Sulfonamides eliminated mainly in the urine as the unchanged drug an the urine as the unchanged drug and metabolic product. nd metabolic product.

• In acid urine, the eliminated are inIn acid urine, the eliminated are insoluble and may precipitate, thus isoluble and may precipitate, thus induced renal disturbance.nduced renal disturbance.

ADME of sulfonamidesADME of sulfonamides

Sulfonamides

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• Increase the effects of tolbutamideIncrease the effects of tolbutamide甲苯磺丁脲甲苯磺丁脲 , warfarin , trexan, warfarin , trexan 甲氨喋甲氨喋呤呤

• The reason is: The reason is: all sulfonamides are all sulfonamides are bound in varying degree to plasma bound in varying degree to plasma protein.protein.

Drugs interactionsDrugs interactions

Sulfonamides

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(1) Oral absorbable agents(1) Oral absorbable agents• Short-acting agentsShort-acting agentsSulfafurazole(SIZ,Sulfafurazole(SIZ, 菌得清菌得清 ))Sulfadimidine,(SN2,Sulfadimidine,(SN2, 磺胺二甲嘧啶磺胺二甲嘧啶 ))• Medium-acting agentsMedium-acting agentsSulfadiazine(SD,Sulfadiazine(SD, 磺胺嘧啶磺胺嘧啶 ))Sulfamethoxazole(SMZ,Sulfamethoxazole(SMZ, 新诺明新诺明 ))• Long-acting agentsLong-acting agentsSulfamonomethoxine(SMMSulfamonomethoxine(SMM ,磺胺间甲氧嘧,磺胺间甲氧嘧啶啶 ))

SulfonamidesSulfonamides AgentsAgents

Sulfonamides

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(2) Oral nonabsorbable agents(2) Oral nonabsorbable agentsSulfasalazine(Sulfasalazine( 柳氮磺吡啶 柳氮磺吡啶 ) ) (3) Topical agents.(3) Topical agents.Mafenide(SML, Mafenide(SML, 磺胺米窿磺胺米窿 ))Sulfadiazine sliver(Sulfadiazine sliver( 磺胺嘧啶银磺胺嘧啶银 ))Sulfacetamide(SA,Sulfacetamide(SA, 磺胺醋酰)磺胺醋酰)

SulfonamidesSulfonamides AgentsAgents

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(4) Combination agents. (4) Combination agents. • Co-trimoxazole(Co-trimoxazole( 复方新诺明)复方新诺明)• Trimethoprim(Trimethoprim( 甲氧苄啶甲氧苄啶 ) in combination ) in combination

with Sulfamethoxazole(1:5) exerts a synerwith Sulfamethoxazole(1:5) exerts a synergistic effects. gistic effects.

• Pharmcokinetics: The ADME of the two agPharmcokinetics: The ADME of the two agent is similar.ent is similar.

• Pharmcodynamics: Co-Pharmcodynamics: Co-block essential enzblock essential enzymes of folate metabolism.ymes of folate metabolism.

SulfonamidesSulfonamides AgentsAgents

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(4) Combination agents. (4) Combination agents. • Co-trimoxazole(Co-trimoxazole( 复方新诺明)复方新诺明)Clinical Use Clinical Use • Chronic and recurrent infections in the uriChronic and recurrent infections in the uri

nary tractnary tract• Bacterial respiratory infectionsBacterial respiratory infections• GI infections (eg. induced by Salmonella)GI infections (eg. induced by Salmonella)

SulfonamidesSulfonamides AgentsAgents

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(4) Combination agents. (4) Combination agents.

• Co-trimoxazole(Co-trimoxazole( 复方新诺明)复方新诺明) Adverse reactionAdverse reaction

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

• The main untoward effects is hypersensitivThe main untoward effects is hypersensitive reactions( eg. involve the skin).e reactions( eg. involve the skin).

SulfonamidesSulfonamides AgentsAgents

Sulfonamides

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Trimethoprim (Trimethoprim ( 甲氧苄啶甲氧苄啶 ))• Dihydrofolate reductase inhibitorDihydrofolate reductase inhibitor• Drug resistance occurs easily when used Drug resistance occurs easily when used

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

Nitrofurantoin(Nitrofurantoin( 呋喃妥因呋喃妥因))• Bactericidal agent Bactericidal agent • Co A inhibitor→DNA damageCo A inhibitor→DNA damage• Resistance is rareResistance is rare

• Clinical applications:Clinical applications: Urinary tract infectionsUrinary tract infections

OtherOther SyntheticSynthetic antimicrobialantimicrobial

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Other Synthetic Other Synthetic antimicrobialantimicrobial

• Trimethoprim( 甲氧苄啶 )• Nitrofurans( 硝基呋喃类 ):• Funacillin( 呋喃西林 )• Furantoin( 呋喃妥因 )• Furazolidone( 呋喃唑酮 , 痢特灵 )

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END OF CLASSEND OF CLASS