Pharmacological properties
pharmacodynamics. Azithromycin is a second-generation macrolide antibiotic belonging to the azalide group.
The mechanism of action of azithromycin is the suppression of bacterial protein synthesis by binding to the 50S ribosome subunit and peptide translocation.
Mechanism of resistance. In general, the resistance of various bacterial species to macrolides is associated with the action of one of three mechanisms: modification of the target cell, inactivation of the antibiotic, or active removal of the antibiotic (efflux) from the cell. Bacteria have various systems for removing substances from the cell. In streptococci, the removal system is largely controlled by the mef genes, which causes the formation of limited resistance to macrolides (phenotype M). Modification of the target by methylase, controlled by the erm gene (phenotype MLSB), can cause cross-resistance to different classes of antibiotics.
Complete cross-resistance to erythromycin, azithromycin, other macrolides and lincosamides, and streptogramin B exists between Streptococcus pneumoniae, group A β-hemolytic streptococci, Enterococcus faecalis, and Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA).
Constitutive mutants in inducible resistant strains with erm(A) or erm(C) can be selected in vitro at low concentrations of ~10-7 CFU in the presence of azithromycin.
Breakpoint concentration. The minimum inhibitory concentrations (MICs) for the organisms for the indicated indications are presented below (see INDICATIONS).
It should be noted that the MIC breakpoints and in vitro spectra of activity presented below are applicable for systemic use. These MICs are not suitable for topical ocular use given the concentrations achieved in situ and the physicochemical conditions that may affect the overall activity of the antibiotic at the site of application.
EUCAST (European Committee on Antimicrobial Susceptibility Testing) has established the following breakpoints for azithromycin:
Haemophilus influenzae: susceptible ≤0.12 mg/L and resistant >4 mg/L;
Moraxella catarrhalis: susceptible ≤0.5 mg/L and resistant >0.5 mg/L;
Neisseria gonorrhoeae: susceptible ≤0.25 mg/L and resistant >0.5 mg/L;
Staphylococcus spp.*: susceptible ≤1.0 mg/L and resistant >2.0 mg/L;
Streptococcus pneumoniae: susceptibility ≤0.25 mg/L and resistance >0.5 mg/L;
Streptococcus A, B, C, G: susceptibility ≤0.25 mg/L and resistance >0.5 mg/L.
*Spp. includes all species of the class.
EUCAST notes that erythromycin may be used to determine susceptibility to azithromycin in these organisms.
The prevalence of acquired resistance may vary locally and over time for individual species, so local resistance information is essential, particularly for the treatment of severe infections. Where appropriate, expert advice should be sought if the local prevalence of resistance is such that the efficacy of the drug in treating at least some types of infections is questionable.
Spectrum of antibacterial activity of azithromycin against bacterial species according to indications
Usually sensitive species
Aerobic gram-negative: Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoae1, Haemophilus influenzae$, Haemophilus parainfluenzae$.
Others: Chlamydia trachomatis*.
Species that may acquire resistance
Aerobic gram-positive: Staphylococcus aureus (methicillin-resistant and methicillin-sensitive), Staphylococcus coagulase negative (methicillin-resistant and methicillin-sensitive), Streptococcus pneumoniae, Streptococcus pyogenes, Streptococci viridans, Streptococcus agalactiae, Streptococcus group G.
Resistant species
Aerobic gram-positive: Corynebacterium spp., Enterococcus faecium.
Aerobic gram-negative: Pseudomonas aeruginosa, Acinetobacter, Enterobacteriaceae.
*Clinical efficacy has been demonstrated on susceptible strains isolated according to approved indications.
$Intermediate natural susceptibility.
1Conjunctivitis caused by Neisseria gonorrhoeae requires systemic treatment (see SPECIAL INSTRUCTIONS).
Clinical Trial Information
Trachomatous conjunctivitis caused by Chlamydia trachomatis. A randomized, double-blind, 2-month study compared Aziter with a single dose of oral azithromycin for the treatment of trachoma in 670 children (aged 1–10 years). The efficacy of Aziter after its use twice daily for 3 days (96.3%) was not significantly different from that of azithromycin, which was used orally (96.6%). Mass therapy, treatment and prevention of trachoma with Aziter (instillation 2 times a day for 3 days) in all categories of the population (from birth) were assessed during the IV stage of a multicenter open non-comparative study conducted in northern Cameroon (112,000 patients).

). In a sample of 2400 children aged 1 to 10 years, the prevalence of active trachoma, which was 31.1% before the instillation of Aziter, decreased to 6.3% after 1 year and to 3.1% in the 2nd and 3rd years.
No serious side effects were observed in the population receiving therapy with this drug.
Purulent bacterial conjunctivitis. A randomized, single-blind study in different geographic locations in Europe, North Africa, and India compared Aziter twice daily for 3 days with tobramycin 0.3% eye drops every 2 hours for 2 days, then 4 times daily for 5 days in 1043 patients with purulent bacterial conjunctivitis, including 109 children aged ≤11 years, 5 neonates (birth to 27 days), and 38 infants and toddlers (28 days to 23 months).
Clinical cure within 9 days with Aziter (87.8%) was not significantly different from the result of tobramycin therapy (89.4%). The microbiological status of cure with Aziter was comparable to that with tobramycin therapy.
Children. The efficacy and safety of Aziter were demonstrated in patients aged ≤18 years in a randomized, blinded, closed study comparing Aziter (2 times daily for 3 days) with tobramycin (2-hourly for 2 days, then 4 times daily for 5 days) in 282 pediatric patients with purulent bacterial conjunctivitis (the subgroup of patients aged 0–24 months included 148 patients). Clinical recovery in the most affected eyes on day 3 was significantly higher in the Aziter group (47%) than in the tobramycin group (28%). On day 7, recovery was observed in 89% of patients receiving Aziter (2 times daily for 3 days) compared with 78% of patients receiving tobramycin. There is no statistical difference between the two study groups regarding the bacteriological status on day 7. Azithromycin was well tolerated in all age groups. No new side effects were detected in children. The short duration of therapy with 1.5% azithromycin, the small number of necessary administrations, and the ease of instillation of drops in children were appreciated by both children and their parents.
Pharmacokinetics. Azithromycin was not detected in the blood plasma of patients with bacterial conjunctivitis after administration of Azithromycin within the recommended doses (sensitivity limit: 0.0002 μg/ml in blood plasma). Pharmacokinetic studies in children have not been conducted.

Indications for Azithromycin
Azithromycin is intended for local antibacterial therapy of conjunctivitis caused by strains sensitive to it in children from the first days of life and in adults, namely:
- purulent bacterial conjunctivitis;
– trachomatous conjunctivitis caused by Chlamydia trachomatis.

Application of Aziter
for eye drops. The physician must provide the patient with information on the proper use of the antibacterial drug.
Adults. Instill 1 drop into the conjunctival sac 2 times a day, morning and evening. The course of therapy is 3 days. There is no need to continue therapy for >3 days. Compliance with the dosage is important for the success of therapy.
Elderly patients. There is no need to adjust the dosage.
How to use.
1. Wash your hands, stand or sit comfortably.
2. Pull the lower eyelid of the affected eye down with your finger.
3. Bring the tip of the open single-dose container as close to the eye as possible, but do not touch the eye with it.
4. Gently squeeze the container so that one drop gets into the eye, and release the lower eyelid.
5. Close your eyes and pinch the inner corner of the instilled eye with your finger for 1 minute.
6. Repeat all the above steps with the second eye, if prescribed by your doctor.
7. Throw away the single-dose container with the remainder of the solution immediately after use. Do not store it for further use.
In case of using several ophthalmic topical agents, the drugs should be used at intervals of at least 15 minutes.
Children. Used in children from birth. Dosage - as indicated for adults in the APPLICATION section. There is no need to adjust the dose for children (see SPECIAL INSTRUCTIONS and Pharmacodynamics).

Contraindications
hypersensitivity to azithromycin or another macrolide, or any other component of the drug.

Side effects
during clinical studies and post-marketing observations of the use of the drug Aziter 15 mg / g, eye drops, solution, the following adverse reactions associated with treatment were reported.
Adverse reactions are distributed by frequency as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), unknown (cannot be determined from the available data).
From the immune system: uncommon - Quincke's edema*, reaction 

and hypersensitivity.
From the organ of vision (at the injection site): very often - eye discomfort (itching, burning, tingling); often - blurred vision, feeling of eyelids sticking together, foreign body sensation; uncommon - conjunctivitis*, allergic conjunctivitis*, keratitis*, eyelid eczema*, eyelid edema*, eye allergy*, conjunctival hyperemia, increased lacrimation, eyelid erythema.
From the skin and subcutaneous tissue: unknown (cannot be estimated based on the available data, disorders are described in accordance with the possible side effect with systemic administration) - toxic epidermal necrolysis$, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)$, Stevens-Johnson syndrome (SJS)$, exfoliative dermatitis$, acute generalized exanthematous pustulosis (AGEP)$. *Adverse reactions were not observed during clinical studies of the drug Azither. These adverse reactions were identified during post-marketing studies of the use of azithromycin. The frequency is calculated using the formula 3/X, where X is the total population involved in all studies, including clinical ones, or corresponds to a frequency of 3/879 - "rare".
$extrapolating systemic exposure. At the same time, after using the drug Azither within the recommended doses, azithromycin was not detected in the blood plasma of patients and did not have a systemic effect.
Children. Clinical studies in pediatrics have proven that the level of safety in children does not differ from that in adults. No new adverse effects were identified. The levels of safety in various subgroups of children were also similar (see PHARMACOLOGICAL PROPERTIES).

Special instructions
the drug is not intended for oral or injection use, including periocular or intraocular injection.
In case of an allergic reaction, therapy should be discontinued.
The patient should be informed that the use of the drug should not be continued for >3 days, even if there are residual signs of bacterial conjunctivitis.
As a rule, a decrease in the severity of symptoms is observed within 3 days of use. If there are no signs of improvement after this period, the prescribed therapy should be reviewed.
In case of bacterial conjunctivitis, contact lenses should not be used during the therapy period.
With systemic use of azithromycin, cases of fulminant hepatitis have been reported, which can cause life-threatening liver failure. With local use in the eyes, this risk is not expected, since the systemic exposure to the active substance is clinically insignificant (see Pharmacokinetics).
Hypersensitivity. As with the use of erythromycin and other macrolides, rare serious allergic reactions have been reported, including angioedema and anaphylaxis (rarely fatal); dermatological reactions, including acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (rarely fatal), drug reaction with eosinophilia and systemic symptoms (DRESS). Some of these reactions associated with azithromycin led to the occurrence of repeated symptoms and required a longer period of observation and treatment.
In case of allergic reactions, the use of the drug should be discontinued and appropriate symptomatic therapy should be initiated. Physicians should take into account that manifestations of allergic symptoms may reappear after cessation of symptomatic therapy.
Childhood. Comparative studies of the efficacy and safety of the use of Aziter, eye drops, for the treatment of trachomatous conjunctivitis in children <1 year of age have not been conducted. However, there are no known safety concerns or differences in pathophysiology of the disease that would exclude its use in children <1 year of age for this indication, given the clinical experience in children ≥1 year of age and the experience in children from birth for the treatment of purulent bacterial conjunctivitis.
Use in neonates. Based on the international consensus on eye and genital tract diseases that can be transmitted to neonates, non-trachomatous (chlamydial) conjunctivitis caused by Chlamydia trachomatis, as well as conjunctivitis caused by Neisseria gonorrhoeae, require systemic therapy.
In neonates and children under 3 months of age, systemic infections (e.g. pneumonia, bacteremia caused by Chlamydia trachomatis) may be accompanied by conjunctivitis. If suspected, differential diagnosis should be performed and, if necessary, systemic therapy should be initiated.
Use during pregnancy or lactation. Since the systemic effects of azithromycin are clinically insignificant, the drug can be used during pregnancy and breastfeeding.
Reproductive function. Data obtained from animal studies do not indicate an effect of azithromycin on reproductive function.

men or women. There are no data on the effects on the human body. However, since the systemic effects of azithromycin are clinically insignificant, no effects on reproductive function are expected.
Ability to influence reaction time when driving vehicles or operating other mechanisms. After instillation, temporary loss of visual acuity may occur. In this case, the patient should wait until normal vision is restored before driving vehicles or operating other mechanisms.

Interactions
Special studies on interaction with the drug Aziter have not been conducted.
Since there is no systemic effect of the drug Aziter, eye drops when instilled into the eyes (there are no noticeable concentrations of azithromycin in the blood plasma, see Pharmacokinetics), no interaction of azithromycin with other drugs is expected when taken orally.
In case of simultaneous use with the drug Aziter of other drugs in the form of eye drops, it is necessary to observe a 15-minute break between applications, and Aziter, eye drops, are instilled last.

Overdose
the total amount of azithromycin intended for the treatment of both eyes is extremely small to cause overdose symptoms in case of intravenous administration or per os use of the contents of a single-dose container.

Storage conditions
at a temperature of 2-8 °C in a place inaccessible to children. Store single-dose containers in a sachet to protect from light.