Binozyt Mechanism of Action

Pharmacotherapeutic group: Antibacterials for systemic use; macrolides; azithromycin. ATC code: J01FA10.
PHARMACOLOGY: Pharmacodynamics: General properties: Mode of action: Azithromycin is an azalide, a sub-class of the macrolide antibiotics. By binding to the 50S-ribosomal sub-unit, azithromycin avoids the translocation of peptide chains from one side of the ribosome to the other. As a consequence of this, RNA-dependent protein synthesis in sensitive organisms is prevented.
Mechanism of resistance: Resistance to azithromycin may be inherent or acquired. There are three main mechanisms of resistance in bacteria: target site alteration, alteration in antibiotic transport and modification of the antibiotic.
Complete cross resistance exists among Streptococcus pneumoniae, betahaemolytic streptococcus of group A, Enterococcus faecalis and Staphylococcus aureus, including methicillin resistant S. aureus (MRSA) to erythromycin, azithromycin, other macrolides and lincosamides.
Following assessment of studies in children, the use of azithromycin is not recommended for the treatment of malaria, neither as monotherapy nor combined with chloroquine or artemisinin based drugs, as non-inferiority to anti-malarial drugs recommended in the treatment of uncomplicated malaria was not established.
Breakpoints: Azithromycin susceptibility breakpoints for typical bacterial pathogens are: NCCLS: Susceptible ≤ 2 mg/l; resistant ≥ 8 mg/l; Haemophilus spp.: susceptible ≤ 4 mg/l; Streptococcus pneumoniae and Streptococcus pyogenes.: susceptible ≤ 0.5 mg/l; resistant ≥ 2 mg/l.
Susceptibility: The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
Pathogens for which resistance may be a problem: prevalence of resistance is equal to or greater than 10% in at least one country in the European Union. (See table.)

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Pharmacokinetics: Absorption: After oral administration the bioavailability of azithromycin is approximately 37%. Peak plasma levels are reached after 2-3 hours (C_max after a single dose of 500 mg orally was approximately 0.4 mg/l).
Distribution: Kinetic studies have shown markedly higher azithromycin levels in tissue than in plasma (up to 50 times the maximum observed concentration in plasma) indicating that the active substance is heavily tissue bound (steady state distribution volume of approximately 31 l/kg). Concentrations in target tissues such as lung, tonsil, and prostate exceed the MIC₉₀ for likely pathogens after a single dose of 500 mg.
In serum the protein binding of azithromycin is variable and depending on the serum concentration varies from 50% in 0.05 mg/l to 12% in 0.5 mg/l.
Excretion: Plasma terminal elimination half-life closely reflects the tissue depletion half-life of 2 to 4 days. About 12% of an intravenously administered dose is excreted in the urine unchanged over a period of 3 days; the majority in the first 24 hours. Biliary excretion of azithromycin, predominantly in unchanged form, is a major route of elimination.
The identified metabolites (formed by N- and O-demethylising, by hydroxylising of the desosamine and aglycone rings, and by the splitting of the cladinose conjugate) are microbiologically inactive.
Pharmacokinetics in special populations: Renal insufficiency: Following a single oral dose of azithromycin 1 g, mean C_max and AUC_0-120 increased by 5.1% and 4.2% respectively, in subjects with mild to moderate renal impairment (glomerular filtration rate of 10-80 ml/min) compared with normal renal function (GFR > 80 ml/min). In subjects with severe renal impairment, the mean C_max and AUC_0-120 increased 61% and 33% respectively compared to normal.
Elderly: The pharmacokinetics of azithromycin in elderly men was similar to that of young adults; however, in elderly women, although higher peak concentrations were observed, no significant accumulation occurred.
Toxicology: Preclinical safety data: In high-dose animal studies, giving active substance concentrations 40 fold higher than those expected in clinical practice, azithromycin has been noted to cause reversible phospholipidosis, generally without discernible toxicological consequences. There is no evidence that this is of relevance to the normal use of azithromycin in humans.