|Pharmacotherapeutic group: antibiotics, ATC code: S01AA26|
Mode of actionAzithromycin 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 resistanceGenerally, 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 below).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 (MRSA).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.
BreakpointsThe list of micro-organisms presented hereafter has been targeted to the indications (see section 4.1.).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 geniusFor other species, EUCAST allows that erythromycin can be used to determine the susceptibility of the listed bacteria to azithromycin.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.
* Clinical effectiveness is demonstrated by sensitive isolated organisms for approved indications.$ Natural intermediate susceptibility.1 Conjunctivitis caused by Neisseria gonorrhoeae require a systemic treatment (see section 4.4).
|Commonly susceptible species|
|Moraxella (Branhamella) catarrhalis|
|Species for which acquired resistance may be a problem|
(methicillin resistant and methicillin susceptible)|
|Staphylococcus,coagulase negative (methicillin resistant and methicillin susceptible)|
|Inherently resistant organisms|
|Aerobic Gram positive|
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 reatment 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.
Paediatric populationThe 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.