Axcel Azithromycin Mechanism of Action

Pharmacotherapeutic group: antibacterials for systemic use; macrolides; azithromycin. ATC code: J01FA.
Pharmacology: Mode of action: Azithromycin is an azalide, a sub-class of the macrolide antibiotics. By binding to the 50S-ribosomal sub-unit, azithromycin avoids the translocation of peptide chains from one side of the ribosome to the other. As a consequence of this, RNA-dependent protein synthesis in sensitive organisms is prevented.
PK/PD relationship: For azithromycin the AUC/MIC is the major PK/PD parameter correlating best with the efficacy of azithromycin. Following the assessment of studies conducted in children, the use of azithromycin is not recommended for the treatment of malaria, neither as monotherapy nor combined with chloroquine or artemisinin based drugs, as noninferiority to anti-malarial drugs recommended in the treatment of uncomplicated malaria was not established.
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. Complete cross resistance exists among Streptococcus pneumoniae, betahaemolytic streptococcus of group A, Enterococcus faecalis and Staphylococcus aureus, including methicillin resistant S. aureus (MRSA) to erythromycin, azithromycin, other macrolides and lincosamides.
Breakpoints: (see table.)

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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.
Commonly susceptible species: Aerobic Gram-negative microorganisms: Haemopilus influenzae*, Moraxella catarrhalis*.
Other microorganisms: Chlamydophila pneumonia, 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: Aerobic Gram-positive microorganisms: Staphylococcus aureus - methicillin resistant and erythromycin resistant strains; Streptococcus pneumoniae - penicillin resistant strains.
Aerobic Gram-negative microorganisms: Escherichia coli, Pseudomonas aeruginosa, Klebsiella spp.
Anaerobic Gram-negative microorganisms: Bacteroides fragilis group.
*Clinical effectiveness is demonstrated by sensitive isolated organisms for approved clinical indications.
Pharmacokinetics: Absorption: After oral administration the bioavailability of azithromycin is approximately 37%. Peak plasma levels are reached after 2-3 hours (C_max after a single dose of 500mg orally was approximately 0.4mg/l).
Distribution: Kinetic studies have shown markedly higher azithromycin levels in tissue than in plasma (up to 50 times the maximum observed concentration in plasma) indicating that the active substance is heavily tissue bound (steady state distribution volume of approximately 31l/kg). Concentrations in target tissues such as lung, tonsil, and prostate exceed the MIC90 for likely pathogens after a single dose of 500mg. In experimental in vitro and in vivo studies azithromycin accumulates in the phagocytes, freeing is stimulated by active phagocytosis. In animal studies this process appeared to contribute to the accumulation of azithromycin in the tissue. In serum the protein binding of azithromycin is variable and depending on the serum concentration varies from 50% in 0.05mg/l to 12% in 0.5mg/l.
Excretion: Plasma terminal elimination half-life closely reflects the tissue depletion half-life of 2 to 4 days. About 12% of an intravenously administered dose is excreted in the urine unchanged over a period of 3 days; the majority in the first 24 hours. Biliary excretion of azithromycin, predominantly in unchanged form, is a major route of elimination. The identified metabolites (formed by N- and 0-demethylising, by hydroxylising of the desosamine and aglycone rings, and by the splitting of the cladinose conjugate) are microbiologically inactive. After a 5 day treatment slightly higher (29%) AUC values were seen in the elderly volunteers (>65 years of age) compared to the younger volunteers (<45 years of age). However, these differences are not regarded as clinically relevant; therefore a dose adjustment is not recommended.
Pharmacokinetics in special populations: 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.
Renal insufficiency: Following a single oral dose of azithromycin 1g, mean C_max and AUC0-120 increased by 5.1% and 4.2% respectively, in subjects the mild to moderate renal impairment (glomerular filtration rate of 10-80ml/min) compared with normal renal function (GFR >80ml/min). In subjects with severe renal impairment, the mean C_max andAUC0-120 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 azithromycin compared to normal hepatic function. In these patients, urinary recovery of azithromycin appears to increase perhaps to compensate for reduced hepatic clearance.
Infants, toddlers, children and adolescents: Pharmacokinetics have been studied in children aged 4 months -15 years taking capsules, granules or suspension. At 10mg/kg on day 1 followed by 5mg/kg on days 2-5, the C_max achieved is slightly lower than adults with 224μg/l in children aged 0.6-5 years and after 3 days dosing and 383μg/l in those aged 6-15 years. The t½ of 36h in the older children was within the expected range for adults.