Adverse events experienced in higher than recommended doses were similar to those seen at normal doses. In the event of overdosage, general symptomatic and supportive measures are indicated as required.
Not applicable
In animal tests in which the dosages used amounted to 40 times the clinical therapeutic dosages, Azibiot 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 Azibiot 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, Azibiot 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 Azibiot and above were observed.
General properties
Pharmacotherapeutic group: antibacterials for systemic use, macrolides, Azibiot,
ATC code: J01FA10
Mode of action
The mechanism of action of Azibiot 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. Azibiot acts bacteriostatic.
PK/PD Relationship
The efficacy of Azibiot 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 Azibiot may be natural or acquired. There are 3 main mechanisms of resistance affecting Azibiot:
- 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 Azibiot 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 Azibiot (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.
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 Azibiot is widely distributed throughout the body.
In pharmacokinetic studies it has been demonstrated that the concentrations of Azibiot 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 Azibiot/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 Azibiot is excreted unchanged in urine within the following three days. Particularly high concentrations of unchanged Azibiot 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 Azibiot are not microbiologically active.
In animal tests, high concentrations of Azibiot have been found in phagocytes. It has also been established that during active phagocytosis higher concentrations of Azibiot are released than are released from inactive phagocytes. In animal models the Azibiot concentrations measured in inflammation foci were high.
Pharmacokinetics in Special Populations
Renal insufficiency
Following a single oral dose of Azibiot 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 Azibiot compared to normal hepatic function. In these patients, urinary recovery of Azibiot appears to increase perhaps to compensate for reduced hepatic clearance.
Elderly
The pharmacokinetics of Azibiot 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.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
