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Pharmacology: Pharmacodynamics: Azithromycin is the first of a subclass of macrolides antibiotics, known as azalides, and is chemically different from erythromycin. Chemically it is derived by insertion of a nitrogen atom into the lactone ring of erythromycin A. The mode of action of azithromycin is inhibition of protein synthesis in bacteria by binding to the 50s ribosomal subunit and preventing translocation of peptides. Azithromycin demonstrates activity in vitro against a wide range of bacteria including: Gram-positive Aerobic Bacteria - Staphylococcus aureus, Streptococcus pyogenes (group A beta - hemolytic streptococci), Streptococcus pneumoniae, alpha - hemolytic streptococci (viridans group) and other streptococci, and Corynebacterium diphtheriae. Azithromycin demonstrates cross-resistance with erythromycin-resistant Gram-positive strains, including Streptococcus faecalis (enterococcus) and most strains of methicillin-resistant staphylococci.
Gram-negative Aerobic Bacteria - Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Acinetobacter species, Yersinia species, Legionella pneumophila, Bordetella pertussis, Bordetella parapertussis, Shigella species, Pasteurella species, Vibrio cholerae and parahaemolyticus, Plesiomonas shigelloides. Activities against Escherichia coli, Salmonella enteritidis, Salmonella typhi, Enterobacter species, Aeromonas hydrophila and Klebsiella species are variable and susceptibility tests should be performed. Proteus species, Serratia species, Morganella species, and Pseudomonas aeruginosa are usually resistant.
Anaerobic Bacteria - Bacteroides fragilis and Bacteroides species, Clostridium perfringens, Peptococcus species and Peptostreptococcus species, Fusobacterium necrophorum and Propionibacterium acnes.
Organisms of Sexually Transmitted Diseases - Azithromycin is active against Chlamydia trachomatis and also shows good activity against Treponema pallidum, Neisseria gonorrhoeae, and Haemophilus ducreyi.
Other Organisms - Borrelia burgdorferi (Lyme disease agent), Chlamydia pneumoniae, Mycoplasma pneumoniae, Mycoplasma hominis, Ureaplasma urealyticum, Campylobacter species and Listeria monocytogenes.
Opportunistic Pathogens Associated with HIV Infections - Mycobacterium avium-intracellulare complex, Pneumocystis carinii and Toxoplasma gondii.
Commonly susceptible species: Aerobic Gram-positive bacteria: Staphylococcus aureus, Streptococcus agalactiae, Streptococci (Groups C, F, G) and Viridans group streptococci. Aerobic Gram-negative bacteria: Bordetella pertussis, Haemophilus ducreyi, Haemophilus influenzae, Haemophilus parainfluenzae, Legionella pneumophila, Moraxella catarrhalis and Neisseria gonorrhoeae.
Other: Chlamydia pneumoniae, Chlamydia trachomatis, Mycoplasma pneumoniae and Ureaplasma urealyticum.
Species for which acquired resistance has been reported: Aerobic Gram-positive bacteria: Streptococcus pneumoniae, Streptococcus pyogenes.
Note: Azithromycin demonstrates cross-resistance with erythromycin-resistant gram-positive strains.
Inherently resistant organisms: Enterobacteriaceae, Pseudomonas.
Pharmacokinetics: Absorption: Following oral administration in humans, azithromycin is widely distributed throughout the body; bioavailability is approximately 37%. The time taken to peak plasma levels is 2-3 hours.
Distribution: In animal studies, high azithromycin concentrations have been observed in phagocytes. In experimental models, higher concentrations of azithromycin are released during active phagocytosis than from non-stimulated phagocytes. In animal models this results in high concentrations of azithromycin being delivered to the site of infection. Pharmacokinetic studies in humans have shown markedly higher azithromycin levels in tissue than in plasma (up to 50 times the maximum observed concentration in plasma) indicating that the drug is heavily tissue bound. Concentrations in target tissues, such as lung, tonsil and prostate exceed the MIC90 for likely pathogens after a single dose of 500mg.
Elimination: Plasma terminal elimination half-life closely reflects the tissue depletion half-life of 2 to 4 days. Approximately 12% of an intravenously administered dose is excreted in the urine over 3 days as the parent drug, the majority in the first 24 hours. Biliary excretion of azithromycin is a major route of elimination for unchanged drug following oral administration. Very high concentrations of unchanged drug have been found in human bile, together with 10 metabolites, formed by N- and O-demethylation, by hydroxylation of the desosamine and aglycone rings, and by cleavage of the cladinose conjugate. Comparison of HPLC and microbiological assays in tissues suggests that metabolites play no part in the microbiological activity of azithromycin.
Pharmacokinetics in Special Patient Groups: Elderly: In elderly volunteers (>65 years), slightly higher AUC values were seen after a 5-day regimen than in young volunteers (<40 years), but these are not considered clinically significant, and hence no dose adjustment is recommended.
Renal Impairment: The pharmacokinetics of azithromycin in subjects with mild to moderate renal impairment (GFR10-80ml/min) were not affected following a single one gram dose of immediate release azithromycin. Statistically significant differences in AUC0-120 (8.8 μg·hr/ml vs. 11.7μg·hr/ml), Cmax (1.0μg/ml vs. 1.6μg/ml) and CLr 2.3ml/min/kg vs. 0.2ml/min/kg) were observed between the group with severe renal impairment (GFR<10ml/min) and the group with normal renal function.
Hepatic Impairment: In patients with mild to moderate hepatic impairment, there is no evidence of a marked change in serum pharmacokinetics of azithromycin compared to those with normal hepatic function. In these patients urinary clearance of azithromycin appears to increase, perhaps to compensate for reduced hepatic clearance.
