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Synthetic antimicrobial agents

Section 6. Synthetic antimicrobial agents. Yun-Bi Lu, PhD 卢韵碧 Dept. of Pharmacology, School of Medicine, Zhejiang University yunbi@zju.edu.cn. Contents. Quinolones ( 喹诺酮类 ) Sulfonamides ( 磺胺类 ) Other Synthetic antimicrobial Trimethoprim ( 甲氧苄啶 ) Nitrofurans ( 硝基呋喃类 ).

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Synthetic antimicrobial agents

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  1. Section 6 Synthetic antimicrobial agents Yun-Bi Lu, PhD 卢韵碧 Dept. of Pharmacology, School of Medicine, Zhejiang University yunbi@zju.edu.cn

  2. Contents • Quinolones ( 喹诺酮类) • Sulfonamides ( 磺胺类) • Other Synthetic antimicrobial Trimethoprim (甲氧苄啶) Nitrofurans (硝基呋喃类)

  3. Contents • Quinolones ( 喹诺酮类) • Sulfonamides ( 磺胺类) • Other Synthetic antimicrobial Trimethoprim (甲氧苄啶) Nitrofurans (硝基呋喃类)

  4. From chloroquine to nalidixic acid

  5. 喹诺酮类(Quinolones) Generation Example time 1 Nalidixic acid 萘啶酸 1962 2 Pipemidic acid 吡哌酸 1973 3 Norfloxacin诺氟沙星 4 Clinfloxacin 克林沙星 1990’s

  6. First generation fluoroquinolones

  7. From ofloxacin to levofloxacin

  8. Fluoroquinolones

  9. Fluoroquinolones • broad antimicrobial activity • effective after oral administration • relatively few side effects • resistance to their action does not develop rapidly.

  10. General properties of Quinolones 1. Antimicrobial activity & spectrum: (1) bactericidal and have significant PAE. (2) aerobic G- bacteria, Pesudomonas, aerobic G+bacteria, Chlamydia spp.（衣原体）, Legionella pneumophila(军团菌) , anaerobic bacteria, mycobacteria(分枝杆菌), multiple-resistance strains.

  11. DNA gyrase Topoisomerase Mechanism of action Key enzymes in DNA replication: bacterial DNA is supercoiled.

  12. porin DNA gyrase Topo isomerase Gram (-) Gram (+) Mechanism of action

  13. DNA gyrase Catalytic subunite Fluoroquinolones: 4 stacked molecules DNA gyrase ATP binding subunite Mechanism of action

  14. decreased permeability active efflux system porin DNA gyrase Topo isomerase mutation of the enzymes Gram (-) Gram (+) Mechanism of resistance

  15. ADME of fluoroquinolones • Absorption: well absorbed; bound by divalent cations • Do not administer with iron, magnesium, calcium • Distribution: all distribute widely (even in CSF), and most concentrate in urine • Metabolism: • hepatic metabolism diminishes the activity of norfloxacin and ciprofloxacin • Several have predominately hepatic clearance (Grepafloxacin, Sparfloxacin, Trovafloxacin) • Excretion: urinary excretion predominates for the first generation fluoroquinolones

  16. ADME of fluoroquinolones

  17. Clinical Uses • Urinary tract infections. • GI and abdominal infections. • Respiratory tract infections. • Bone, joint and soft tissues infections, Osteomyelitis. • Meningitis • STD: Neisseria gonorrhea (奈瑟氏淋球菌)and Chlamydia (衣原体，Quinolone resistance in gonorrhea increasing)

  18. Adverse reactions • Gastrointestinal effects. • CNS side effects. • Allergic reaction. • Hepatotoxicity, nephrotoxicity. • Joint/cartilage toxicity, Tendinopathy • Achilles tendon rupture • Limited FDA approval for children

  19. Fluoroquinolones agents • Norfloxacin(诺氟沙星) • Ciprofloxacin (环丙沙星) • Ofloxacin (氧氟沙星) • Levofloxacin (左氧氟沙星) • Lomefloxacin(洛美沙星) • Fleroxacin (氟罗沙星) • Sparfloxacin (司帕沙星) • Clinafloxacin (克林沙星) • Gatifloxacin (加替沙星)

  20. Contents • Quinolones ( 喹诺酮类) • Sulfonamides ( 磺胺类) • Other Synthetic antimicrobial Trimethoprim (甲氧苄啶) Nitrofurans (硝基呋喃类)

  21. Gerhard Domagk Nobel Laureate 1939 Inhibitors of Folate Synthesis 2,4-Diaminoazobenzen-4’-sulfonamide Prontosil

  22. First Aid Packet carried by U.S. Soldiers in World War II http://home.att.net/~steinert/wwii.htm

  23. Sulfonamides Antimicrobial activity: • A wide antimicrobial spectrum. • Exerting onlybacteriostatic effect.

  24. Pteridine+PABA Dihydropteroate synthase Blocked by sulfonamides Dihydropteroic acid glutamate Dihydrofolic acid NADPH Dihydrofolate reductasease Blocked by trimethoprim NADPH Tetrahydrofolic acid Mechanism of action

  25. Mechanism of Resistance • A lower affinity for sulfonamides by the dihydropteroate synthase • Decreased cell permeability or active efflux of the drug • An alternative pathway to synthesis the essential metabolites • An increased production of essential metabolites

  26. ADME of sulfonamides • Approximately 70%-100% of an oral dose is absorbed. • Distributing throughout all tissues of the body,even in CSF ( sulfadiazine and sulfisoxazole, may be effective in meningeal infections) ;readily passing though the placenta. • Metabolized in the liver by acetylation.

  27. ADME of sulfonamides • Eliminated mainly in the urine as the unchanged drug and metabolic product. In acid urine, the eliminated may precipitate, thus induced renal disturbance.

  28. Clinical uses • Systemic infections. • Intestinal infections. • Infections of burn and wound.

  29. Adverse reactions • Urinary tract disturbances • Hypersensitivity reaction • Hematopoietic system disturbances • Kernicterus (胆红素脑病) • Hepatitis • GI effects Drugs interactions • All sulfonamides are bound in varying degree to plasma protein.

  30. Classification: • Oral absorbable agents • Short-acting agents • Medium-acting agents • Long-acting agents • Oral nonabsorbable agents • Topical agents • Combination agents

  31. Oral absorbable agents • Short-acting agents Sulfafurazole (SIZ,菌得清) • Medium-acting agents Sulfadiazine (SD,磺胺嘧啶) Sulfamethoxazole (SMZ,新诺明) • Long-acting agents Sulfadoxine (SDM，周效磺胺)

  32. Oral nonabsorbable agents Sulfasalazine (柳氮磺吡啶 ) Topical agents. Mafenide (SML, 甲磺灭脓) Sulfadiazine sliver (磺胺嘧啶银) Sulfacetamide (SA,磺胺醋酰）

  33. Combination agents Co-trimoxazole (复方新诺明) 1) Features • Trimethoprim(甲氧苄啶)in combination with Sulfamethoxazole(1:5) exerts asynergistic effects. • The ADME of the two agents is similar. • Co-block essential enzymes offolate metabolism.

  34. Pteridine+PABA Dihydropteroate synthase Blocked by sulfonamides Dihydropteroic acid glutamate Dihydrofolic acid NADPH Dihydrofolate reductasease Blocked by trimethoprim NADPH Tetrahydrofolic acid

  35. 2)Clinical Uses • Chronic and recurrent infections in the urinary tract • Bacterial respiratory infections • GI infections (e.g. induced by Salmonella) • pneumocystis carinii pneumonia (肺囊虫性肺炎)

  36. 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

  37. Other Synthetic antimicrobial • Trimethoprim (甲氧苄啶) • Nitrofurans (硝基呋喃类) Nitrofurantoin(呋喃妥因)

  38. Section 7 Antifungal agents

  39. Antifungal agents Onychomycosis

  40. Antifungal agents Fungal infections traditionally have been divided to two distinct classes: systemic and superficial. So, the major antifungal agents are described with “systemic” and “topical”. Onychomycosis （甲癣）

  41. Invasive fungal disease • Ubiquitous pathogens act as opportunists • Candida species (念珠菌属) • Aspergillus species (曲霉菌属) • Cryptococcus (隐球菌属) • Endemic mycoses • Histoplasmosis(组织胞浆菌病) • Coccidioidomycosis(球孢子菌病) • Blastomycosis(芽生菌病)

  42. Oral infection with Candida (Thrush鹅口疮) http://vasculitis.med.jhu.edu/treatments/cytoxan.html www.thachers.org/ internal_medicine.htm

  43. Invasive Aspergillosis AA= aortic arch, a = aneurysm SC = subclavian artery Silva ME, Malogolowkin MH, Hall TR, Sadeghi AM, Krogstad P.Mycotic aneurysm of the thoracic aorta due to Aspergillus terreus: case report and review. Clin Infect Dis. 2000 Nov;31(5):1144-8.

  44. Classification of antifungal agents • Polyenes: Amphotercin B（两性霉素B） • Azoles Ketoconazole（酮康唑） Fluconazol（氟康唑） • Allylamine Terbinafine（特比萘芬） • Pyrimidine analogues Flucytosine（氟胞嘧啶）

  45. Antifungal Medications

  46. Polyenes Amphotercin B（两性霉素B） broad-spectrum

  47. Amphotercin B 1. Mechanism of action

  48. Amphotercin B 2. Clinical Uses: • Amphotericin B remains the drug of choice for all life-threatening mycotic infections (It is often as the initial regimen). • E.g. Cryptococcal meningitis

  49. Amphotercin B 3. Adverse reactions: (1) fever, chill, hyperpnea（喘息）, myalgia（肌痛）and hypotension, etc.（~75%） (2) nephrotoxic (3) renal tubular acidosis（肾小管酸化） and renal wasting K+ and Mg 2+ (4) hematological Toxicity: hypochromic （低血红蛋白性）and normocytic（正常色素性） anemia, etc.

  50. Amphotercin B 3. Adverse reactions: (5) hepatotoxicity (6) cardiac toxicity (7) CNS side effects (8) hypersensitive reaction

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