第三十八章大环内酯类、林可霉素类及万古霉素类

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Clarithromycin (克拉霉素) More acid stability, more active against mycobacterium avium complex, M leprae and Toxoplasma gondii, lower frequency of GI intolerance. It is metabolized in the liver. The major metabolite is 14-hydroxyclarithromycin, which has antibacterial activity. All of them are eliminated in the urine. Dosage ↓ for patients with renal dysfunction. Azithromycin (阿齐霉素) A 15-atom lactone macrolide ring compound, is active against M avium complex and T gondii. Azithromycin is slightly less active than erythromycin against staphylococci and streptococci and slighyly more active against H influenzae. It is highly active against chlamydia. It differs from erythromycin mainly in pharmacokinetic properties. It penetrates into most tissues, except cerebrospinal fluid, and phagocytic cells extremely well, with tissue concentrations exceeding serum concentrations by 10to 100-fold. Drug is slowly released from tissues to produce an elimination half-life approaching 3 days. It is rapidly absorbed and well tolerated orally. It should be administered 1h before or 2h after meals. It does not inactivate cytochrome P450 enzymes and is free of the drug interactions that occur with erythromycin. II. Clindamycin 1. Chemistry and Classification
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2. Classification ① 14-atom lactone ring erythromycin (红霉素), oleandomycin (竹桃霉素), clarithromycin (克拉霉素*), roxithromycin (罗红霉素), dirithromycin (地红霉素) ② 15-atom lactone ring) azithromycin (阿齐霉素 *semisythetic) ③ 16-atom lactone ring medecamycin (麦迪霉素), acetylmedecamycin (乙酰麦迪霉素), kitasamycin (吉他霉素), acetylkitasamycin (乙酰吉他霉素), josamycin ( 交 沙 霉 素 ), spiramycin ( 螺 旋 霉 素 ), acetylspiramycin (乙酰螺旋霉素), rokitamycin (罗他霉素) 3. Pharmacodynamics ① Antibacterial spectrum: narrow,
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G
+
(pneumococci,
streptococci,
staphylococci,
corynebacteria; mycoplasma, legionella, chlamydia trachomatis, helicobacter, listeria, certain mycobacteria), G (neisseria species, bordetalla pertussis),
some rickettsia species, treponema pallidum, and campylobacter species. ② Antibacterial activity Inhibitory or bactericidal, particularly at higher concentrations, for susceptible organisms. Activity is enhanced at alkaline pH. ③ Mechanism of antibiotic action Inhibition of protein synthesis occurs via binding to the 50S ribosomal RNA. Protein synthesis is inhibited because aminoacyl translocation reactions and the formation of initiation complexes are blocked.
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in patients with anuria. Adjustment for renal failure is not necessary. Erythromycin is not removed by dialysis. Large amounts of an administered dose are excreted in the bile and lost in feces, and only 5% is excreted in the urine. Absorbed drug is distributed widely except to the brain and cerebrospinal fluid. Erythromycin is taken up by polymorphonuclear leukocytes and macrophages. It traverses the placenta and reaches the fetus. 5. Drugs that are commonly used in therapy ① Erythromycin (红霉素) ② Clarithromycin (克拉霉素) ③ Azithromycin (阿齐霉素) Clinical uses of Erythromycin a. It is the drug of choice in croynebacterial infections (diphtheria, corynebacterial sepsis, erythrasma); in respiratory , neonatal ocular inflammation, or genital chlamydial infections; and in treatment of community-acquired pneumonia because its spectrum of activity includes the pneumococcus, mycoplasma, and legionella. b. Erythromycin is also useful as a penicillin substitute in penicillin-allergic individuals with infections caused by staphylococci (assuming that the isolate is susceptible), streptococci, or pneumococci. c. It has been recommended as prophylaxis against endocarditis during dental procedures in individuals with valvular heart disease, though clindamycin, which is better tolerated, has largely replaced it. Adverse reactions of Erythromycin a. Gastrointestinal effects Anorexia, nausea, vomiting, and diarrhea. Gastrointestinal intolerance, which is due to a direct stimulation of gut motility, is the most frequent reason for discontinuing erythromycin and substituting another antibiotic. b. Liver toxicity Erythromycin, particularly the estolate, can produce acute cholestatic hepatitis (fever, jaundice, impaired liver function), probably as a hypersensitivity reaction. Most patients recover from this, but hepatitis recurs if the drug is readministered. Other allergic reactions include fever, eosinophilia, and rashes. c. Drug interactions Erythromycin metabolites can inhibit cytochrome P450 enzymes and thus ↑ the serum concentrations of numerous drugs, including theophylline, oral anticoagulants, cyclosporine, and mehtylprednisolone. Erythromycin ↑ serum concentrations of oral digoxin by ↑ its F.