Zenith Suspension/Zenith OD Suspension 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: Pharmacotherapeutic group: Azithromycin is a semi-synthetic azalide derivative with a 15-membered lactone ring. Azalides belong to the macrolide antibiotics. ATC code: J01FA10.
Pharmacodynamics: Zenith Suspension: Mode of action: By binding to the 50S-ribosomal subunit, 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 rRNA 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 clarithomycin, 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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Zenith OD Suspension: Azithromycin is a semi-synthetic azalide antibiotic, a subclass of macrolide antibiotics, with a broader spectrum of activity than erythromycin or clarithromycin. Azithromycin exerts its antibacterial action by binding to the 23S rRNA of the 50S ribosomal subunit of susceptible bacteria. It blocks protein synthesis by inhibiting the transpeptidation/translocation step of protein synthesis and by inhibiting the assembly of the 50S ribosomal unit.
Antimicrobial Spectrum of Activity: Azithromycin is active in vitro and in clinical infections against most isolates of the following microorganisms: See Table 3.

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Azithromycin has demonstrated in vitro activity against strains of the following microorganisms; however, clinical significance is unknown. (See Tables 4 and 5.)

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Resistance to azithromycin may be inherent or acquired. Azithromycin demonstrates cross-resistance with erythromycin-resistant Gram-positive strains. Most strains of Enterococcus faecalis, Bacteroides fragilis and methicillin-resistant staphylococci are resistant to azithromycin.
Pharmacokinetics: Zenith Suspension: 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%.
Zenith OD Suspension: Azithromycin is rapidly but incompletely absorbed from the gastrointestinal tract after oral administration; its absorption, however, exceeds that of erythromycin. Peak plasma levels are achieved 2-3 hours after oral administration with absolute bioavailability of about 37%.
After administration of azithromycin oral suspension (10 mg/kg as a single dose on Day 1 followed by 5 mg/kg daily on Days 2 to 5) in fasting children 1 to 5 years old, mean peak plasma concentration (C_max) on Day 5 was 0.216 mcg/mL at 1.9 hours with an area under the curve (AUC_0-24) of 1.822 mcg·hr/mL. When the same dosage regimen was administered in fasting children 5 to 15 years old, mean C_max on Day 5 was 0.383 mcg/mL at 2.4 hours with an AUC of 3.109 mcg·hr/mL.
Pharmacokinetics in children given a total dose of 30 mg/kg delivered as a single dose have not been studied.
When azithromycin oral suspension (at a total dose of 60 mg/kg in divided doses given as 20 mg/kg/day for 3 days or 12 mg/kg/day over 5 days with a maximum daily dose of 500 mg) was given to children 3 to 16 years old with pharyngitis/tonsillitis, C_max was 1.05 ± 0.44 mcg/mL at 3 ± 2 hours with an AUC_0-24 of 7.92 ± 2.87 mcg·hr/mL for the 3-day regimen; C_max was 0.534 ± 0.361 mcg/mL at 2.2 ± 0.8 hours with an AUC_0-24 of 3.94 ± 1.9 mcg·hr/mL for the 5 day regimen.
Food does not have a substantial effect on the extent of absorption (AUC) of azithromycin oral suspension, although the absorption rate may be increased. Compared with fasting administration, a single 500 mg dose of azithromycin oral suspension with food was associated with a 56% increase in peak plasma drug concentration but no change in AUC.
Azithromycin is widely distributed into most body fluids and tissues. High concentrations are found in the pulmonary tissue, tonsillar tissue, gastric mucosa, liver, prostate, and gynecological tissues, even 4 to 5 days after a single dose. These sustained tissue concentrations are significantly above the minimum inhibitory concentration (MIC₉₀) values for most common pathogens. Lower concentrations are found in fat, muscle and bone samples.
Serum concentrations decline polyphasically. The initial decline in plasma levels is caused by the rapid and extensive distribution of the drug into tissues. Azithromycin concentration in most tissues generally exceeds that in serum by 10- to 100-fold.
Only very low concentrations of azithromycin (less than 0.01 mcg/mL) have been detected in cerebrospinal fluid (CSF) in the presence of noninflamed meninges. Concentrations in peritoneal fluid are also very low.
Azithromycin crosses the placenta and is distributed into cord blood and amniotic fluid. The drug is distributed into milk.
Azithromycin's serum protein binding decreases with increasing drug concentration (from 12% at 0.5 mcg/mL to 52% at 0.05 mcg/mL).
Azithromycin undergoes metabolism primarily via N-demethylation of the desosamine sugar or at the 9a position on the macrolide ring. Other metabolic pathways include O-demethylation and hydrolysis and/or hydroxylation of the cladinose and desosamine sugar moieties and the macrolide ring. Up to 10 metabolites have been identified, and all are not microbiologically active.
The terminal elimination phase of azithromycin from the serum is via hepatic metabolism, biliary excretion and transintestinal passage. Although high azithromycin concentrations in the bile relative to serum concentrations suggest biliary excretion as an important route of elimination, transintestinal excretion may be the principal route of excretion for unchanged drug. The half-life (t_1/2) of the drug in peripheral leukocytes ranges from 34 to 57 hours. The average tissue t_1/2 is about 1 to 4 days. Only a small portion (6%) of a 500 mg oral dose of azithromycin appears in urine as unchanged drug over a one-week period.
An elimination t_1/2 of 54.5 hours has been reported in children 4 months to 15 years old given a single or multiple doses of azithromycin.
In patients with severe renal impairment [glomerular filtration rate (GFR) <10 mL/min], the C_max and AUC were increased by 61% and 35%, respectively, after administration of a single 1 g dose of azithromycin.
Toxicology: Preclinical safety data: Zenith Suspension: 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.