Antibiotic. ATC Code:
Pharmacology: Pharmacodynamics: Mode of action:
Azithromycin is a second-generation macrolide antibiotic belonging to the azalide group.
It inhibits the synthesis of bacterial proteins by binding to the 50S ribosomal subunit and preventing peptide translocation.
Mechanism of resistance:
Generally, the resistance of different bacterial species to macrolides has been reported to occur by three mechanisms associated with target site alteration, antibiotic modification, or altered antibiotic transport (efflux). Various efflux pump systems have been described in bacteria. An important efflux system in streptococci is conferred by the mef
genes and results in a macrolide-restricted resistance (M phenotype). Target modification is controlled by erm
encoded methylases (MLSB
phenotype) and results in cross-resistance to several classes of antibiotics (see as follows).
A complete cross-resistance exists among erythromycin, azithromycin, other macrolides and lincosamides and streptogramin B for Streptococcus pneumoniae
, beta-haemolytic streptococci of group A, Enterococcus
spp. and Staphylococcus aureus
, including methicillin-resistant S. aureus
Penicillin-sensitive S. pneumoniae
are more likely to be susceptible to azithromycin than are penicillin-resistant strains of S. pneumoniae
. Methicillin-resistant S. aureus
(MRSA) is less likely to be susceptible to azithromycin than methicillin-sensitive S. aureus
Constitutive mutants in inducibly resistant strains with erm
(A) or erm
(C) can be selected in vitro
at low frequencies ~ 10-7
cfu in the presence of azithromycin.
Note that the breakpoints and in-vitro
activity spectrum presented hereafter are those applicable to systemic use. These breakpoints may not be applicable to topical ocular application of the drug product due to the local concentrations that are reached and the local physicochemical conditions that may influence the overall activity of the agent at the site of application.
According to the EUCAST (European Committee on Antimicrobial Susceptibility Testing) the following breakpoints have been defined for azithromycin: Haemophilus influenzae
: S ≤ 0.12 mg/l and R >4 mg/l; Moraxella catarrhalis
: S ≤ 0.5 mg/l and R >0.5 mg/l; Neisseria gonorrhoeae
: S ≤ 0.25 mg/l and R >0.5 mg/l; Staphylococcus
spp*: S ≤ 1.0 mg/l and R >2.0 mg/l; Streptococcus pneumoniae
: S ≤ 0.25 mg/l and R >0.5 mg/l; Streptococcus
A, B, C, G: S ≤ 0.25 mg/l and R >0.5 mg/l.
*spp includes all the species of the genus.
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 is such that the utility of the agent in at least some types of infections is questionable. (See table.)
Click on icon to see table/diagram/image
Information from clinical trials:
Trachomatous conjunctivitis caused by Chlamydia trachomatis
: Azyter was evaluated in a two-month, randomised, double-masked study comparing Azyter with a single oral dose of azithromycin for the treatment of trachoma in 670 children (1-10 years). The primary efficacy variable was the clinical cure at Day 60, i.e.
a grade TF0 (simplified WHO grading scale). At Day 60, clinical cure rate of Azyter instilled twice daily for 3 days (96.3%) was non-inferior to that of oral azithromycin (96.6%).
The clinical efficacy of Azyter (instilled twice daily for 3 days) in mass curative and prophylactic treatment of trachoma in an entire population (from birth) in a northern Cameroon district (112 000 subjects) was assessed in a multicentre, open-label, single-arm, phase IV study. Three annual treatment periods were performed. The primary efficacy endpoint was the prevalence of active trachoma, i.e. trachomatous inflammation-follicular or trachomatous inflammation-intense (TF+TI0 or TF+TI+). For analysis, clinical assessment of trachoma was performed each year in a sample of 2400 children aged ≥1 and < 10 years old selected using a random cluster sampling. The prevalence of active trachoma (TF+TI0 or TF+TI+) was 31.1% at Year 0 (before Azyter instillations) and decreased to 6.3% at Year 1, 3.1% at Year 2 and 3.1% at Year 3.
In the whole population, there was no serious adverse event in relation with the study drug.
Purulent bacterial conjunctivitis: Azyter was evaluated in a randomised, investigator-masked study comparing Azyter, instilled twice daily for 3 days, with tobramycin 0.3% eye drops, instilled every two hours for 2 days then four times daily for 5 days, for the treatment of purulent bacterial conjunctivitis in 1043 patients (ITT set), including 109 children up to the age of 11 years from whom 5 were newborn infants (0 to 27 days) and 38 infants and toddlers (28 days to 23 months of age). In the Per Protocol set (n=471), there were no newborns and only 16 infants and toddlers. The clinical study was performed in different areas in Europe, North Africa, and India. The primary efficacy variable was the clinical cure at Day 9 in the PP set, defined as a score of 0 for both the bulbar conjunctival injection and the purulent discharge. At Day 9, clinical cure rate of Azyter (87.8%) was non-inferior to that of tobramycin (89.4%). Microbiological resolution rate of Azyter was comparable to that of tobramycin.
The efficacy and safety of Azyter in paediatric patients ≤ 18 years of age was demonstrated in a randomised, investigator-masked study compared with tobramycin in 282 analysed patients diagnosed with purulent bacterial conjunctivitis (including 148 patients in the subgroup 0 day - < 24 months). Patients received either Azyter, instilled twice daily for 3 days or tobramycin 0.3% eye drops, instilled every two hours for 2 days then four times daily for 5 days. The primary efficacy endpoint was the clinical cure in the worse eye on D3 for patients with D0 positive bacterial cultures. Clinical cure in the worse eye on D3 was demonstrated to be significantly superior for Azyter (47%) than for tobramycin (28%). At D7, 89% of patients treated with Azyter were cured versus 78% with tobramycin. No statistical difference was found between treatment groups for the bacteriological resolution at D7.
Azyter (instilled twice daily for 3 days) was well tolerated in all age groups in this large study in paediatric population. The events observed in paediatric subjects were a subset of those previously observed in adults; no new adverse events were identified in paediatric subjects. Furthermore, no age-related patterns of clinical concern were evident. The short duration of Azithromycin 1.5% treatment, the low number of instillations needed and the easiness of instilling drops in children were appreciated by both children and parents.
Azithromycin was not detected in the blood of patients with bacterial conjunctivitis after instillation of Azyter at the recommended dose (detection limit: 0.0002 μg/mL of plasma).
Pharmacokinetic studies have only been performed in adults.
Toxicology: Pre-Clinical Safety Data:
In animals, azithromycin caused reversible phospholipids. This effect was seen after oral exposures which were about 300 times in excess of the maximum human exposure after ocular administration indicating little relevance to clinical use.
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.
Mutagenic potential: There was no evidence of a potential for genetic and chromosome mutations in in vivo
and in vitro
Reproductive toxicity: No teratogenic effects were observed in embryotoxicity studies in rates after oral administration of azithromycin. In rats, azithromycin dosages of 100 and 200 mg/kg body weight/day led to mild retardations in fetal ossification and in maternal weight gain. In peri- and postnatal studies in rats, mild retardations following treatment with 50 mg/kg/day azithromycin and above were observed. These effects were seen after oral administation at exposures which were about 1000 times in excess of the maximum human exposures after ocular administration. Because of the high safety margin, these findings do not point to a relevant risk for human reproduction.
Ocular toxicity: Ocular administration of Azyter eye drops to animals twice or three times a day during 28 days did not demonstrate any local or systemic toxic effect.