Synthetic antimicrobial drugs Chapter 34 Synthetic antimicrobial drugs Shutcm-MBL 1

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 Shutcm-MBL

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: 100-230 h Shutcm-MBL

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. Shutcm-MBL

Inhibition of bacterial folate synthesis Mechanism of actions Inhibition of bacterial folate synthesis Shutcm-MBL

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 Shutcm-MBL

3. Local infections SD-Ag: fire burn with pseudomonas aeruginosa Shutcm-MBL

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 Shutcm-MBL

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 Shutcm-MBL

Part 3. Quinolones Commonly used are the third generation: fluoroquinolones Shutcm-MBL

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 Shutcm-MBL

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). Shutcm-MBL

Mechanism of action Inhibit DNA gyrase, and topoisomerase Ⅳ Shutcm-MBL

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. Shutcm-MBL

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. Shutcm-MBL

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 Shutcm-MBL