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Pharmacology: Pharmacodynamics: Azithromycin is an azalide, a sub-class of macrolide antibiotics. By binding to the 50S-ribosomal subunit, 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.
PK/PD relationship: For azithromycin, the AUC/MIC is the major PK/PD parameter correlating best with the efficacy of azithromycin. Following the assessment of studies conducted 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.
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, beta hemolytic streptococcus of group A, Enterococcus faecalis and Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA) to erythromycin, azithromycin, other macrolides and lincosamides.
Pharmacokinetics: Absorption: The biological availability of azithromycin after oral administration is approximately 37%. Peak plasma levels are achieved 2-3 hours after taking the medicinal product.
Distribution: After oral administration, azithromycin is distributed throughout the entire body. Pharmacokinetic studies have shown clearly higher azithromycin levels in the tissues than in the plasma (up to 50 times the maximum observed concentration in plasma). This indicates that the substance is bound in the tissues in considerable quantities. Concentrations in the infected tissues, such as lungs, tonsil and prostate are higher than the MRC90 of the most frequently occurring pathogens after a single dose of 500 mg. The protein binding of azithromycin in serum is variable and varies, depending on the serum concentration, from 52% at 0.05 mg/l to 12% at 0.5 mg/l. The steady state distribution volume is 31.1 l/kg.
Elimination: The terminal plasma-elimination half-life closely follows the tissue depletion half-life from 2 to 4 days. Approximately 12% of an intravenously administered dose of azithromycin is, over a period of 3 days, excreted unchanged in the urine. High concentrations of unchanged azithromycin were found in human bile. In this, ten metabolites were also detected (formed by N- and O- desmethylation, by hydroxylation of the desosamin and aglycon rings and by splitting the cladinose conjugate). A comparison of fluid chromatography and microbiological assessment methods shows that the metabolites are microbiologically inactive. In animal models, high concentrations of azithromycin were found in phagocytes. Also, it has been shown that during active phagocytosis higher concentrations of azithromycin are released than during inactive phagocytosis. In animal models, this process was shown to contribute to the accumulation of azithromycin in infectious tissue.
