Not applicable
Not applicable.
In animal tests in which the dosages used amounted to 40 times the clinical therapeutic dosages, Zeto was found to have caused reversible phospholipidosis, but as a rule, no true toxicological consequences were observed which were associated with this. The relevance of this finding to humans receiving Zeto in accordance with the recommendations is unknown.
Carcinogenic potential:
Long-term studies in animals have not been performed to evaluate carcinogenic potential as the drug is indicated for short-term treatment only, and there were no signs indicative of carcinogenic activity.
Mutagenic potential:
There was no evidence of a potential for genetic and chromosome mutations in in-vivo and in-vitro test models.
Reproductive toxicity:
In animal studies of the embryotoxic effects of the substance, no teratogenic effect was observed in mice and rats. In rats, Zeto dosages of 100 and 200 mg/kg bodyweight/day led to mild retardations in foetal ossification and in maternal weight gain. In peri- and postnatal studies in rats, mild retardation in physical development and delay in reflex development following treatment with 50 mg/kg/day Zeto and above were observed.
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 multiple 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 for animals and humans is unknown.
Carcinogenic potential:
Long-term studies in animals have not been performed to evaluate carcinogenic potential as the drug is indicated for short-term treatment only and there were no signs indicative of carcinogenic activity.
Mutagenic potential:
There was no evidence of a potential for genetic and chromosome mutations in in-vivo and in-vitro test models.
Reproductive toxicity:
In animal studies for embryotoxic effects of the substance, no teratogenic effect was observed in mice and rats. In rats, azithromycin doses of 100 and 200 mg/kg bodyweight/day led to mild retardation of foetal ossification and in maternal weight gain. In peri- and postnatal studies in rats, mild retardation following treatment with 50 mg/kg/day azithromycin and above was observed.
General properties
Pharmacotherapeutic group: antibacterials for systemic use, macrolides, Zeto,
ATC code: J01FA10
Mode of action
The mechanism of action of Zeto is based on the suppression of bacterial protein synthesis, that is to say that it binds to the ribosomal 50s sub-unit and inhibits the translocation of peptides. Zeto acts bacteriostatic.
PK/PD Relationship
The efficacy of Zeto 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.
Mechanism of resistance
Resistance to Zeto may be natural or acquired. There are 3 main mechanisms of resistance affecting Zeto:
- 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: methylisation 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) (MLSB-phenotype).
- Enzymatic deactivation of macrolides is only of limited clinical significance.
In the presence of the M-phenotype, complete cross resistance exists between Zeto 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
According to EUCAST (European Committee on Antimicrobial Susceptibility Testing) the following breakpoints have been defined for Zeto (2009-06-01):
| Species | Susceptible | Resistant |
| Staphylococcus spp. | ≤ 1 mg/l | > 2 mg/l |
| Streptococcus (Group A,B,C,G) | ≤ 0,25 mg/l | > 0,5 mg/l |
| Streptococcus pneumoniae | ≤ 0,25 mg/l | > 0,5 mg/l |
| Haemophilus influenzae | ≤ 0,12 mg/l | > 4 mg/l |
| Moraxella catarrhalis | ≤ 0,5 mg/l | > 0,5 mg/l |
| Neisseria gonorrhoeae | ≤ 0,25 mg/l | > 0,5 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.
Table of Susceptibility
| Commonly susceptible species |
| Aerobic Gram-negative microorganisms |
| Haemophilus influenzae * |
| Moraxella catarrhalis * |
| Neisseria gonorrhoeae |
| Other microorganisms |
| Chlamydophila pneumoniae |
| Chlamydia trachomatis |
| Legionella pneumophila |
| Mycobacterium avium |
| Mycoplasma pneumonia * |
| Species for which acquired resistance may be a problem |
| Aerobic Gram-positive microorganisms |
| Staphylococcus aureus * |
| Streptococcus agalactiae |
| Streptococcus pneumoniae * |
| Streptococcus pyogenes * |
| Other microorganisms |
| Ureaplasma urealyticum |
| Inherently resistant organisms |
| Staphylococcus aureus - methicillin resistant and erythromycin resistant strains |
| Streptococcus pneumoniae - penicillin resistant strains |
| Escherichia coli |
| Pseudomonas aeruginosa |
| Klebsiella spp. |
* Clinical effectiveness is demonstrated by sensitive isolated organisms for approved clinical indication.
General properties
Pharmacotherapeutic group: Antibacterials for systemic use. ATC code: J01FA10
Mode of action:
Zeto is a macrolide antibiotic belonging to the azalide group. The molecule is constructed by adding a nitrogen atom to 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. The mechanism of action of azithromycin is based upon the suppression of bacterial protein synthesis by means of binding to the ribosomal 50S sub-unit and inhibition of peptide translocation.
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.
Azithromycin demonstrates cross resistance with erythromycin resistant gram positive isolates. A decrease in macrolide susceptibility over time has been noted particularly in Streptococcus pneumoniae and Staphylococcus aureus. Similarly, decreased susceptibility has been observed among Streptococcus viridans and Streptococcus agalactiae (Group B) streptococcus against other macrolides and lincosamides.
Breakpoints
Azithromycin susceptibility breakpoints for typical bacterial pathogens, as published by EUCAST are:
| Organism | MIC breakpoints (mg/L) | |
| Susceptible (S≤) | Resistant (R>) | |
| Staphylococcus spp. | 1 | 2 |
| Streptococcus groups A, B, C and G | 0.25 | 0.5 |
| Streptococcus pneumoniae | 0.25 | 0.5 |
| Haemophilus influenzae | 0.12 | 4 |
| Moraxella catarrhalis | 0.25 | 0.5 |
| Neisseria gonorrhoeae | 0.25 | 0.5 |
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.
Table: Antibacterial spectrum of Azithromycin
| Commonly susceptible species |
| Aerobic Gram-positive microorganisms |
| Staphylococcus aureus Methycillin-susceptible |
| Streptococcus pneumoniae Penicillin-susceptible |
| Streptococcus pyogenes (Group A) |
| Aerobic Gram-negative microorganisms |
| Haemophilus influenzae Haemophilus parainfluenzae |
| Legionella pneumophila |
| Moraxella catarrhalis |
| Neisseria gonorrhoeae |
| Pasteurella multocida |
| Anaerobic microorganisms |
| Clostridium perfringens |
| Fusobacterium spp. |
| Prevotella spp. |
| Porphyromonas spp. |
| Other microorganisms |
| Chlamydia trachomatis |
| Species for which acquired resistance may be a problem |
| Aerobic Gram-positive microorganisms |
| Streptococcus pneumoniae Penicillin-intermediate Penicillin-resistant |
| Inherently resistant organisms |
| Aerobic Gram-positive microorganisms |
| Enterococcus faecalis |
| Staphylococci MRSA, MRSE* |
| Anaerobic microorganisms |
| Bacteroides fragilis group |
* Methycillin-resistant staphylococci have a very high prevalence of acquired resistance to macrolides and have been placed here because they are rarely susceptible to azithromycin.
Absorption
Bioavailability after oral administration is approximately 37%. Peak concentrations in the plasma are attained 2-3 hours after taking the medicinal product.
Distribution
Orally administered Zeto is widely distributed throughout the body.
In pharmacokinetic studies it has been demonstrated that the concentrations of Zeto measured in tissues are noticeably higher (as much as 50 times) than those measured in plasma.
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.
Binding to serum proteins varies in dependence on exposure in concentration range from 12% in 0.5 microgram/ml up to 52% in 0.05 microgram Zeto/ml serum. The mean volume of distribution at steady state (VVss) has been calculated to be 31.1 l/kg.
Elimination
Terminal plasma elimination half-life closely reflects the elimination half-life from tissues of 2-4 days.
Approximately 12% of an intravenously administered dose of Zeto is excreted unchanged in urine within the following three days. Particularly high concentrations of unchanged Zeto have been found in human bile. In the same source, 10 metabolites were also detected, which were formed through N- and O-demethylation, hydroxylation of desosamine- and aglycone rings and degradation of cladinose conjugate. Comparison of the results of liquid chromatography and microbiological analyses has shown that the metabolites of Zeto are not microbiologically active.
In animal tests, high concentrations of Zeto have been found in phagocytes. It has also been established that during active phagocytosis higher concentrations of Zeto are released than are released from inactive phagocytes. In animal models the Zeto concentrations measured in inflammation foci were high.
Pharmacokinetics in Special Populations
Renal insufficiency
Following a single oral dose of Zeto 1 g, mean Cmax and AUC0-120 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 Cmax and AUC0-120 increased 61% and 33% respectively compared to normal.
Hepatic insufficiency
In patients with mild to moderate hepatic impairment, there is no evidence of a marked change in serum pharmacokinetics of Zeto compared to normal hepatic function. In these patients, urinary recovery of Zeto appears to increase perhaps to compensate for reduced hepatic clearance.
Elderly
The pharmacokinetics of Zeto in elderly men was similar to that of young adults; however, in elderly women, although higher peak concentrations (increased by 30-50%) were observed, no significant accumulation occurred.
Infants, toddlers, children and adolescents
Pharmacokinetics have been studied in children aged 4 months - 15 years taking capsules, granules or suspension. At 10 mg/kg on day 1 followed by 5 mg/kg on days 2-5, the Cmax achieved is slightly lower than adults with 224 ug/l in children aged 0.6-5 years and after 3 days dosing and 383 ug/l in those aged 6-15 years. The t1/2 of 36 h in the older children was within the expected range for adults.
Absorption
Bioavailability after oral administration is approximately 37%. Peak plasma concentrations are attained 2 to 3 hours after taking the medicinal product.
Distribution
Orally administered azithromycin is widely distributed throughout the body. In pharmacokinetic studies 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.
Binding to serum proteins varies according to plasma concentration and ranges from 12% at 0.5 microgram/ml up to 52% at 0.05 microgram azithromycin/ml serum. The mean volume of distribution at steady state (VVss) has been calculated to be 31.1 l/kg.
Elimination
The terminal plasma elimination half-life closely reflects the elimination half-life from tissues of 2-4 days.
Approximately 12% of an intravenously administered dose of azithromycin is excreted unchanged in urine within the following three days. Particularly high concentrations of unchanged azithromycin have been found in human bile. Also in bile, ten metabolites were detected, which were formed through N- and O- demethylation, hydroxylation of desosamine and aglycone rings and cleavage of cladinose conjugate. Comparison of the results of liquid chromatography and microbiological analyses has shown that the metabolites of azithromycin are not microbiologically active.
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.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
No special requirements
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
