1. Synthetic antimicrobial drugs
Chapter 34
Synthetic antimicrobial drugs
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2. Part 1. Sulfonamides Prontosil (1932) Gerhard Domagk
The first commercially available antibacterial agents
Prontosil (1932)
Prontosil is metabolized to sulfanilamide
Gerhard Domagk
Sulfonamides are derivatives of sulfanilamide
1939 Nobel Prize in Medicine
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3. Classes and pharmacokinetics of sulfonamides
Absorbed and excreted rapidly
Sulfisoxazole/Sulfafurazole (SIZ), T1/2: 5-6 h
Sulfamethoxazole (SMZ), T1/2: 11 h
Sulfadiazine (SD), T1/2: 10 h
Poorly absorbed, active in bowel lumen-topically used
Sulfasalazine/salicylazosulfapyridine (SASP) , Sulfacetamide (SA),
Silver sulfadiazine
Long-acting
Sulfadoxine (SDM′) T1/2: h
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4. Antibacterial spectrum and activity
1. Wide range of antimicrobial activity against both gram-positive and gram-negative bacteria; 2. Resistant strains have become common; 3. Exert only a bacteriostatic effect, and cellular and humoral defense mechanisms of the host are essential for final eradication of the infection.
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5. Inhibition of bacterial folate synthesis
Mechanism of actions
Inhibition of bacterial folate synthesis
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6. Clinical uses and selection of drugs
1.General infections SIZ: urinary infection; SD: epidemic cerebrospinal meningitis SMZ+TMP (trimethoprim) : urinary, respiratory and digestive tract infections 2. Enteric infection SASP: ulcerative colitis
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7. 3. Local infections SD-Ag: fire burn with pseudomonas aeruginosa
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8. Adverse reactions
1.Renal damage: Caused by: precipitation of the drugs in kidney Methods to prevention： a. Administration of NaHCO3 to alkalinize urine; b. Drink water; 2. Allergic reactions 3. Myelosuppression 4. Others: reaction of CNS
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9. Part 2. Trimethoprim (TMP)
The antibacterial spectrum of trimethoprim is similar to that of sulfamethoxazole, although the former drug usually is 20 to 100 times more potent than the latter. Trimethoprim–Sulfamethoxazole in Combination: 1:20. Synergistic interaction: sulfonamide inhibits the incorporation of para-aminobenzoic acid (PABA) into folic acid, and trimethoprim prevents the reduction of dihydrofolate to tetrahydrofolate; Pharmacokinetic accordance: T1/2 similar with SMZ
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10. Part 3. Quinolones
Commonly used are the third generation: fluoroquinolones
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11. Pharmacokinetics
Absorption: oral bioavailability of 80-95%; Distribution: widely in body fluids and tissues; Excretion: T1/2 from 3 h to longer than 10 h; Most quinolones are cleared predominantly by the kidney
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12. Antibacterial spectrum
Potent bactericidal agent: active against many bacteria resistant to penicillins, cephalosporins, and aminoglycosides.
Broad spectrum of activity:
1. Most Gram-negative bacteria;
2. Gram-positive bacteria (except Streptococcus pneumoniae and Enterococcus faecalis);
3. Chlamydia and some mycobacteria (except anaerobes).
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13. Mechanism of action
Inhibit DNA gyrase, and topoisomerase Ⅳ
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14. Therapeutic uses
1. Urinary tract infections; 2. Prostatitis; 3. Sexually transmitted diseases; 4. Gastrointestinal and abdominal infections; 5. Respiratory tract infections; 6. Bone, joint, and soft tissue infections; 7. Other infections.
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15. Resistance
Resistance to quinolones is relatively uncommon (1) Mutation that results in a DNA gyrase that is less susceptible to the drug’s action; (2) Increased active drug efux from the cell.
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16. Adverse reactions
1. Gastrointestinal disturbances: nausea, vomiting, abdominal pain, diarrhea 2. Disturbances of CNS (rarely): dizziness, headache, tremor, seizures 3. Allergic reaction (rarely) 4. Cartilage damage and cause an arthropathy: avoiding use in children, pregnant women, and nursing mother.
[‘kɑ:tilidʒ]软骨
[ɑ:'θrɔpəθi] 关节病
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