Zithracin Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of action: Azithromycin is the first of a subclass of macrolide 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 chemical name of azithromycin is 9-deoxy-9a-aza-9a-methyl-9a-homoerythromycin A. The molecular weight is 749.0. Azithromycin binds to the 23S rRNA of the 50S ribosomal subunit. It blocks protein synthesis by inhibiting the transpeptidation/translocation step of protein synthesis and by inhibiting the assembly of the 50S ribosomal subunit.
Antibacterial spectrum: Organisms that are commonly susceptible to azithromycin include: Aerobic and facultative gram-positive bacteria (erythromycin-susceptible isolates): S.aureus, Streptococcus agalactiae,* S. pneumoniae,* Streptococcus pyogenes,* other β-hemolytic streptococci (Groups C, F, G), and viridans streptococci.
Macrolide-resistant isolates are encountered relatively frequently among aerobic and facultative gram-positive bacteria, in particular among methicillin-resistant S. aureus (MRSA) and penicillin-resistant S. pneumoniae (PRSP).
Aerobic and facultative gram-negative bacteria: Bordetella pertussis, Haemophilus ducreyi,* Haemophilus influenzae,* Haemophilus parainfluenzae,* Legionella pneumophila, Moraxella catarrhalis,* and Neisseria gonorrhoeae.* Pseudomonas spp. and most Enterobacteriaceae are inherently resistant to azithromycin, although azithromycin has been used to treat Salmonella enterica infections.
Anaerobes: Clostridium perfringens, Peptostreptococcus spp., and Prevotella bivia.
Other bacterial species: Borrelia burgdorferi, Chlamydia trachomatis, Chlamydophila pneumoniae,* Mycoplasma pneumoniae,* Treponema pallidum, and Ureaplasma urealyticum.
Opportunistic pathogens associated with HIV infection: Eukaryotic microorganisms, Pneumocystis jirovecii and Toxoplasma gondii.
* The efficacy of azithromycin against the indicated species has been demonstrated in clinical trials.
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 to 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 tissues 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 500 mg.
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, hydroxylation of the desosamine and aglycone rings, and 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 GFR 10-80 ml/min were not affected following a single 1 gram dose of immediate-release azithromycin. Statistically significant differences in AUC_0-120 (8.8 μg·h/ml vs. 11.7 μg·h/ml), C_max (1.0 μg/ml vs. 1.6 μg/ml), and CLr (2.3 ml/min/kg vs. 0.2 ml/min/kg) were observed between the group with GFR <10 ml/min and GFR >80 ml/min.
Hepatic Impairment: In patients with mild (Class A) to moderate (Class B) 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.