Antibiotics Macrolides Antimicrobials Prof Gamal A Soliman Pharmacology
Antibiotics - Macrolides Antimicrobials Prof/ Gamal A. Soliman Pharmacology Dept Pharmacy College 1
Macrolides § § § Macrolides are bacteriostatic antibiotics that inhibit the synthesis of bacterial protein and are particularly active against many gram-positive and some gram-negative bacteria. Macrolide antibiotics are so named as they possess a macrocyclic lactone ring to which one or more deoxy sugars are attached. The antibacterial activity of macrolides is related to the presence of the lactone ring. The first macrolide to be discovered is Erythromycin, isolated from Streptomyces erythreus. Clarithromycin and Azithromycin (Zithromax) are semisynthetic derivatives of erythromycin. NOTES o Erythromycin (brand name, Erythrocin) o Clarithromycin (brand name, Klacid) o Azithromycin (brand name, Zithromax)
Macrolides - Classification § Macrolides are classified into 2 groups: 1. First generation macrolides (Natural): Ex: Erythromycin – 1952. § Erythromycin is the natural macrolide that isolated from Streptomyces erythreus. 2. Second generation macrolides (Semi-synthetic): § These are the semi-synthetic macrolides. § They are similar in structure to erythromycin. Ex: Acetylspiramycin, Medecamycin, Josamycin - 1970 s. Clarithromycin, Azithromycin (Zithromax), Roxithromycin - 1980 s. § Clarithromycin is derived from erythromycin by addition of a methyl group. § Azithromycin is derived from erythromycin by addition of a methylated nitrogen into the lactone ring of erythromycin.
Macrolides - Pharmacokinetics 1 - Absorption § Macrolides are readily absorbed from the GI tract if not inactivated by gastric acid v Erythromycin Ø Oral: § § § Erythromycin is inactivated by gastric acid SO it is incompletely absorbed after oral administration. Therefore oral erythromycin should be administered as Enteric coated tablets In addition, oral erythromycin is prepared in some acid-stable preparations : o Acid-resistant esters (erythromycin estolate, erythromycin ethyl succinate, erythromycin propionate). o Acid-resistant salt (erythromycin stearate). § § SO, erythromycin is orally absorbed in the form of ester or as salt Erythromycin estolate is the best absorbed oral preparation. NOTE: o Enteric coated tablet: an oral dosage form in which a tablet is coated with a material to prevent or minimize dissolution in the stomach but allow dissolution in the small intestine.
Ø Injections: § Erythromycin can be given by IV injection (in the form of erythromycin lactobionate). lactobionate § Not given by I/M injection as severe pain occurs at the site of injection. Ø Topical: § Erythromycin can also be used topically. v Clarithromycin & Azithromycin Ø Oral § They are acid-stable antibiotics, so they can be taken orally with no need of protection from gastric acid. Ø Injection: § They can be given by IV injection. Ø Topical: § They can also be used topically
2 - Distribution § § After absorption, macrolides diffuse readily into most body fluids. The passage of macrolides across the blood-brain barrier is low SO, low concentrations are achieved in the CSF. They pass through the placenta and reach the fetus. Macrolides diffuses into phagocytic cells in a high concentration SO macrolides are actively transported to the site of infection. During the process of phagocytosis, large concentrations of macrolides are released. NOTE: o Concentrations of macrolides in the infected tissues are higher than those in non-infected tissues. 3 - Elimination - Excretion § Macrolide antibiotics are excreted mainly in the bile and lost in feces.
Antimicrobial spectrum § Macrolides are moderately broad spectrum antimicrobial drugs. v Erythromycin § § § Erythromycin acts as bacteriostatic antibiotic against Gram-positive bacteria like Staphylococci, Streptococci, Pneumococci and Corynebacterium diphtheria. It is active against some Gram negative bacteria such as Helicobacter pylori, Bordetella pertussis It is also effective against some anaerobic bacteria such as Propionibacterium acnes. v Clarithromycin § § § The antimicrobial spectrum of clarithromycin is identical to those of erythromycin. The gram-positive activity of clarithromycin is superior to that of erythromycin and azithromycin. Clarithromycin is more active against Helicobacter pylori (gram negative bacteria). v Azithromycin § Antimicrobial spectrum of azithromycin is identical to those of erythromycin. § Azithromycin is more active against Bordetella pertussis (gram negative bacteria).
Action and Mechanism of action § Macrolides are bacteriostatic antibiotics § The main site of action of macrolides is the bacterial ribosomes through which they interfere with the ability of bacteria to produce important proteins necessary for them to survive. Macrolides works by binding to the 50 s ribosomal subunit of bacteria so interfere with the process of amino acids polymerization and result in synthesis of non-functional or defective protein. Defective protein fails to function correctly. § § NOTE: o Macrolides do not interfere with protein synthesis in human cells because human ribosomes are structurally different from those of bacteria.
Adverse effects 1 - Gastrointestinal disturbances § GI disturbances are the most common side effects of macrolides. § They are most common with erythromycin than other macrolides. § GI disturbances include nausea, vomiting, gastric pain and diarrhea. 2 - Liver injury - 1 to 5% of treated patients (depending upon the duration of treatment). o Increase in the serum levels of liver enzymes – AST and ALT enzymes. 3 - Other adverse effects: o Ototoxicity (high dose erythromycin) o Allergy. NOTE: o Compared with erythromycin, the semi-synthetic macrolides cause less adverse effects.
Indications (clinical uses) : 1. Upper respiratory tract infections caused by Streptococci or Pneumococci such as sinusitis, tonsillitis and pharyngitis. 2. Lower respiratory tract infections caused by Streptococci or Pneumococci such as bronchitis and pneumonia. NOTE: o Macrolides are the drugs of choice for streptococcal infections when penicillin cannot be used. 3. Diphtheria due to Corynebacterium diphtheria (in addition to antitoxin). NOTE: o Diphtheria infection is treated using two types of medication: – Antibiotics to kill bacteria – Diphtheria antitoxins to neutralize the effect of the toxin produced by the bacteria.
4. Used as a part of triple therapy for treatment of Helicobacter pylori infection associated with peptic ulcer. § The rate of eradication of H. pylori with “triple therapy” is over 85%. § Clarithromycin is the drug of choice. NOTE: o Triple therapy for Helicobacter pylori infection include Clarithromycin, Amoxicillin and Omeprazole. 5. Treatment and prophylaxis of pertussis (whooping cough) due to Bordetella pertussis. § Azithromycin is the 1 st choice. 6. Used topically: Ø for treatment of Acne vulgaris due to Propionibacterium acnes. NOTE: o Macrolides are used as penicillin alternatives in penicillinallergic patients:
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