Mechanism of Action

Azithromycin 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.

Pharmacodynamic Properties

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.

There are two dominant genes that determine the resistance of isolates of Streptococcus pneumoniae and Streptococcus pyogenes: mef and erm. The mef gene encodes a flow pump that mediates resistance to macrolides 14- and 15- only. The mef gene has also been described in a variety of other species. The erm gene codes for a 23S-rRNA methyltransferase that adds methyl groups to adenine 2058 of 23S rRNA (numbering system of E. coli rRNA).

The methylated nucleotide is located in a domain V and is thought to interact with the lincosamides and streptogramin B, in addition to macrolides, resulting in a phenotype known as MLSB resistance. Genes erm (B) and erm (A) are clinical isolates of S. pneumoniae and S. pyogenes.

The pump AcrAB-TolC of Haemophilus influenzae is responsible for the innate MIC values higher for macrolides.

In clinical isolates, mutations in 23S rRNA, specifically in nucleotides 2057–2059 or 2611 in domain V, or mutations in ribosomal protein L4 or L22, are rare.

A complete cross resistance exists among erythromycin, azithromycin, other macrolides and lincosamides for Streptococcus pneumoniae, beta-haemolytic streptococci of group A, Enterococcus spp. and Staphylococcus aureus, including methicillin resistant Staphylococcus aureus (MRSA). Penicillin susceptible Streptococcus pneumoniae are more likely to be susceptible to azithromycin than are penicillin resistant strains of Streptococcus pneumoniae. Methicillin resistant Staphylococcus aureus (MRSA) is less likely to be susceptible to azithromycin than methicillin susceptible Staphylococcus aureus (MSSA).

Breakpoints

The EUCAST susceptibility breakpoints for typical bacterial pathogens are:

  • Staphylococcus spp.; susceptible ≤1 mg/l; resistant >2 mg/l
  • Haemophilus spp.: susceptible ≤0,12 mg/l; resistant >4 mg/l
  • Streptococcus pneumoniae and Streptococcus A, B, C, G: susceptible ≤0.25 mg/l; resistant >0.5 mg/l
  • Moraxella catarrhalis: ≤0.5 mg/l; resistant >0.5 mg/l
  • Neisseria gonorrhoeae: ≤0.25 mg/l; resistant >0.5mg/l

Susceptibility

The bacterial species susceptibility to azithromycin is presented below. 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:

Commonly susceptible species

Aerobic Gram-positive microorganisms:

Staphylococcus aureus (methicillin-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 pneumoniae
Chlamydia trachomatis
Chlamydia psittaci
Mycoplasma pneumoniae
Mycoplasma hominis

Species for which acquired resistance may be a problem

Aerobic Gram-positive microorganisms:*

Streptococcus pneumoniae penicillin-intermediate and penicillin-resistant

Inherently resistant organisms

Aerobic Gram-positive microorganisms:

Enterococcus faecalis
Staphylococci MRSA, MRSE *

Anaerobic microorganisms:

Bacteroides fragilis group

* Methicillin-resistant staphylococci have a very high prevalence of acquired resistance to macrolides and have been placed here because they are rarely susceptible to azithromycin.

Pharmacokinetic Properties

Absorption

Bioavailability after oral administration is approximately 37%. Peak plasma concentrations are attained 2 to 3 hours after taking the medicinal product. The administration of azithromycin capsules after a substantial meal reduces bioavailability.

In patients hospitalized with community-acquired pneumonia treated with a single daily intravenous infusion of 500 mg azithromycin, over one hour, in a solution with a concentration of 2 mg/ml, for 2 to 5 days, the mean Cmax ± D achieved was of 3.63 ± 1.60 µg/ml, while the trough levels concentration at 24 hours was 0.20 ± 0.15 µg/ml and the AUC24 of 9.60 ± 4.80 µg.h/ml.

Mean Cmax, trough levels concentration at 24 hours and AUC24 values were of 1.14 ± 0.14 µg/ml, 0.18 ± 0.02 µg/ml and 8.03 ± 0.86 µg.h/ml, respectively, in normal volunteers receiving intravenous infusion of 500 mg azithromycin at a concentration of 1 mg/ml, for 3 hours.

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.

Concentrations in target tissues such as lung, tonsil, and prostate exceed the MIC90 for likely pathogen agents after a single dose of 500 mg. High azithromycin concentrations were detected in gynaecological tissue 96 hours after a single dose of 500 mg azithromycin.

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.

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.

In a multiple-dose study in 12 normal volunteers using a 500 mg (1 mg/ml) one-hour intravenous dosage regimen for five days, the amount of administered azithromycin dose excreted in urine in 24 hours was about 11% after the 1st dose and 14% after the 5th dose. These values are higher than the reported 6% as being excreted unchanged in urine after oral administration of azithromycin. 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.

Pharmacokinetics in special patient groups

Renal insufficiency

Following a single oral dose of azithromycin 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>80ml/min). In subjects with severe renal impairment, the mean Cmax and AUC0-120 increased 61% and 35% 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 azithromycin compared to normal hepatic function. In these patients, urinary recovery of azithromycin appears to increase perhaps to compensate for reduced hepatic clearance.

Elderly

The pharmacokinetics of azithromycin 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. In elderly volunteers (>65 years), higher (29%) AUC values were always observed after a 5-day course than in younger volunteers (<45 years). However, these differences are not considered to be clinically relevant; no dose adjustment is therefore recommended.

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 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.

Electrophysiological investigations have shown that azithromycin prolongs the QT interval.

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 post-natal studies in rats, mild retardation following treatment with 50 mg/kg/day azithromycin and above was observed.

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