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Protein Synthesis Inhibitors. Tetracyclines Macrolides Chloramphenicol Aminoglycosides Clindamycin Streptogramins. Alan M. Reynared, Ph.D. QUICK REVIEW - Protein Synthesis. Tetracyclines - Structure. Excretion R 1 R 2 R 3 R 4 mg/hr
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Protein Synthesis Inhibitors Tetracyclines Macrolides Chloramphenicol Aminoglycosides Clindamycin Streptogramins Alan M. Reynared, Ph.D.
Tetracyclines - Structure Excretion R1 R2 R3 R4 mg/hr tetracycline (Achromycin) H OH CH3 H 65 chlortetracycline (Aureomycin) H OH CH3 Cl 32 oxytetracycline (Terramycin) OH OH CH3 H 90 demethylchlortetracycline (Declomycin) H OH H Cl 35 doxycycline (Vibramycin) OH CH3 H H 16 minocycline (Minocin) H H H N(CH3) 9
Tetracyclines - Uses Gram- Bacteria Helicobacter pylori (duodenal ulcer) Borrelia recurrentis (Lyme disease, relapsing fever) Other Organisms Mycoplasma pneumoniae acne
Tetracycline - Mechanism Inhibits protein synthesis Static Chelates divalent cations -- Ca++, Mg++
Tetracycline - Adverse Effects headache, nausea, vomiting discoloration of bones and teeth photosensitivity liver damage superinfection
Superinfection A new infection appearing during treatment for a primary infection The organism will be resistant to the antibiotic used for the primary infection Organisms causing superinfection Staphylococcus aureus - enterocolitis Candida albicans - vagina, mouth Clostridium difficile - pseudomembranous colitis Risk factors in hospital > 6 days 6 > age > 60 broad spectrum antibiotic
Tetracylines Administration Oral administration but interference by food, Ca++, Mg++ Excretion renal, fecal enterohepatic
Chloramphenicol - structure/features Features Broad Spectrum Inexpensive Oral administration Virtually non-toxic
Chloramphenicol - uses/toxicity Uses Haemophilus influenzae (meningitis) Typhus Rocky Mountain Spotted Fever eye infections Adverse Effects superinfection aplastic anemia
Chloramphenicol - mechanism Inhibits protein synthesis Static
Macrolides - structure / names erythromycin azithromycin clarithromycin
Macrolides - uses whooping cough pharyngitis Community-acquired pneumonia Penicillin-allergic patients staphylococcus streptococcus pneumococcus
Macrolides - mechanism Inhibits protein synthesis Static
Macrolides - toxicity / drug interactions Toxicity nausea, vomiting, diarrhea cholestatic hepatitis (esp. estolate) Drug Interactions inhibit P450 system
Macrolides Administration erythromycin destroyed by gastric acid - enteric coated tablets - erythromycin stearate - erythromycin estolate food decreases absorption of all macrolides
Aminoglycosides - structure / names streptomycingentamicin kanamycin tobramycin neomycin netilmicin paromomycin amikacin spectinomycin
Aminoglycosides - uses Amikacin serious Gram-negative infections endocarditis (+ a penicillin or cephalosporin) Streptomycin plague (Yersinia pestis) tuleremia (Francisella tulerensis) tuberculosis (Mycobacterium tuberculosis)
Aminoglycosides - mechanism inhibits protein synthesis ribosomal binding is very tight cidal at high doses bacterial cell permeability
Aminglycosides - adverse effects - deafness - vertigo - kidney damage
Aminoglycosides - spectinomycin Use Reserve drug for gonorrhea
Clindamycin USES Staphylococcus aureus Streptococcus pyogenes Bacteroides fragilis Clostridium tetani
Clindamycin - mechanism Inhibits protein synthesis static
Clindamycin - adverse effects superinfection pseudomembranous colitis (ulcerative colitis) Clostridium difficile
Streptogramins Synercid synergistic combination quinupristin dalfopristin activity against staphylococci streptococci vancomycin-resistant enterococci (VRE)
Drug Resistance Types of resistance chromosomal plasmid-mediated Mechanisms of resistance enzymatic destruction of drug altered target of drug decreased influx of drug increased efflux of drug
Drug Resistance 1955 - epidemic of dysentary in Tokyo Multiple Drug Resistance streptomycin 10-8 tetracycline 10-8 chloramphenicol 10-8 sulfisoxazole 10-8 all four 10-32 Transmissible Drug Resistance patient excreting MDR S. dysenteriae and E. coli
Drug Resistance Bacterial Conjugation
Drug Resistance Plasmid specifying resistance to 2 antibiotics
Drug Resistance MDR spread rapidly all over the world
Drug Resistance Increase in resistance with increased production of antibiotics
Drug Resistance - specific antibiotics penicillin -lactamase altered penicillin-binding protein aminoglycosides acetylation AcCoA + AG AcAG + CoA phosphorylation ATP + AG P-Ag + ADP adenylylation ATP + AG AMP-Ag + PPi
Drug Resistance - specific antibiotics chloramphenicol acetylation AcCoA + CM AcCM + CoA erythromycin altered ribosome tetracycline active efflux of drug
Sulfonamides Gerhard Domagk, 1895 - 1964 V.P., I. G. Farbenindustrie