Ruzit Mechanism of Action

Pharmacotherapeutic group: Azithromycin is a semi-synthetic azalide derivative with a 15-membered lactone ring. Azalides belong to the macrolide antibiotics. ATC code: J01FA10.
Pharmacology: Pharmacodynamics: Mode of Action: By binding to the 50S-ribosomal sub-unit, azithromycin avoids the translocation of peptide chains from one side of the ribosome to the other. Azithromycin acts as a bacteriostatic.
PK/PD relationship: The efficacy of azithromycin is best described by the relationship AUC/MIC, where AUC describes the area under the curve and MIC represents the mean inhibitory concentration of the microbe concerned.
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.
Mechanism of resistance: Resistance to azithromycin may be natural or acquired. There are 3 main mechanisms of resistance affecting azithromycin: Efflux: Resistance may be due to an increase in the number of efflux pumps on the cell membrane. In particular, 14- and 15-link macrolides are affected (M-phenotype).
Alterations of the cell structure: Methylation of the 23s rRNS may reduce the affinity of the ribosomal binding sites, which can result in microbial resistance to macrolides, lincosamides and group B streptogramins (SB) (so-called MLSB-phenotype).
Enzymatic deactivation of macrolides is only of limited clinical significance.
In the presence of the M-phenotype, complete cross resistance exists between azithromycin and clarithromycin, erythromycin and roxithromycin. With the MLSB-phenotype, additional cross resistance exists with clindamycin and streptogramin B. A partial cross resistance exists with spiramycin.
Breakpoints: Testing of azithromycin is done by using the usual dilution series. The following minimum inhibitory concentrations for susceptible and resistant germs were determined: See Table 1.

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Prevalence of acquired resistance in Germany: 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.
Microbiological diagnosis with detection of the pathogen and its susceptibility to azithromycin should be attempted, particularly in the case of serious infections or treatment failures. (See Table 2.)

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Pharmacokinetics: Absorption: After oral administration, peak plasma levels are reached after 2 to 3 hours; plasma terminal elimination half-life closely reflects the tissue depletion half-life of 2 to 4 days. After a 5 day treatment slightly higher AUC values were seen in the elderly patients (>65 years of age) compared to the younger patients (<40 years of age). However, these differences are not regarded as clinically relevant; therefore, a dose adjustment is not recommended.
In animal tests, high concentrations of azithromycin have been found in phagocytes. It has also been established that during active phagocytosis higher concentrations of azithromycin are released from inactive phagocytes. In animal models this results in high concentrations of azithromycin being delivered to the site of infection.
Non-linearity: Study data suggest non-linear pharmacokinetics of azithromycin in the therapeutic range.
Distribution: It has been demonstrated that the concentrations of azithromycin measured in tissues are noticeably higher (as much as 50 times) than those measured in plasma, which indicates that the agent strongly binds to tissues. Concentrations in target tissues such as lung, tonsil, and prostate exceed the MIC90 for likely pathogens after a single dose of 500 mg.
Binding to serum proteins varies according to plasma concentration and ranges from 12% at 0.5 μg/mL up to 52% at 0.05 μg azithromycin/mL serum. The mean volume of distribution at steady state (VV_ss) has been calculated to be 31.1 L/kg.
Elimination: About 12% of an intravenously administered dose is excreted unchanged within 3 days; the majority is excreted in the first 24 hours. Particularly high concentrations of unchanged azithromycin have been found in human bile. Also in bile, 10 metabolites were detected, which were formed through N- and O-demethylation, hydroxylation of desosamine and aglycone rings and cleavage of cladinose conjugate. Corresponding studies indicate that the metabolites of azithromycin are not microbiologically active.
Following a single oral dose of azithromycin 1 g, pharmacokinetics were unchanged in subjects with a glomerular filtration rate 10-80 mL/min. At a glomerular filtration rate <10 mL/min, there were statistically significant differences compared with subjects with normal renal function in AUC_0-120 (8.8 μg x h/mL vs. 11.7 μg x 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).
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 patients with normal hepatic function. In these patients, urinary recovery of azithromycin appears to increase perhaps to compensate for reduced hepatic clearance.
The mean bioavailability of azithromycin after oral administration is approximately 37%.
Toxicology: Preclinical safety data: Phospholipidosis (intracellular phospholipid accumulation) has been observed in several tissues (e.g. eye, dorsal root ganglia, liver, gallbladder, kidney, spleen, and/or pancreas) of mice, rats, and dogs given high doses of azithromycin. Phospholipidosis has been observed to a similar extent in the tissues of neonatal rats and dogs. The effect has been shown to be reversible after cessation of azithromycin treatment. The significance of the finding in a clinical context is unknown.
Electrophysiological studies have shown that azithromycin prolongs the QT interval.
There was no evidence of a potential for genetic and chromosome mutations in in-vivo and in-vitro test models.
Long-term studies in animals have not been performed to evaluate carcinogenic potential as the medicinal product is indicated for short-term treatment only and there were no signs indicative of carcinogenic activity.
No teratogenic effects were observed in animal studies of embryotoxicity in mice and rats. In rats, azithromycin doses of 100 and 200 mg/kg bodyweight/day led to mild retardations in foetal ossification and in maternal weight gain. In peri-/postnatal studies in rats, mild retardations following treatment with 50 mg/kg/day azithromycin and above were observed (retardation in physical development and reflex behaviour).
In neonatal studies, rats and dogs did not show higher sensitivity to azithromycin than adult animals of the respective species.