Description
Azithromycin (83905-01-5) is a long-acting macrolide antibiotic structurally related to erythromycin A
(EA), having a methyl-substituted nitrogen at position 9a in the aglycone ring.
Azithromycin is reported to be highly effective in the treatment of respiratory and urinary
infections; it has the advantages of being acid-stable and requiring a shorter course of
treatment than EA.
Chemical Properties
White Crystalline Powder
Originator
Pliva (Yugoslavia)
Definition
ChEBI: A macrolide antibiotic useful for the treatment of bacterial infections.
Indications
Azithromycin in a 500-mg dose three times a week has been shown to yield a
60% reduction in inflammatory papules in 83% of patients enrolled in a 12-
week study. There is no associated pseudotumor cerebri and, therefore,
it can be used for an acne flare during early Accutane therapy.
Manufacturing Process
To a solution of 0.54 g (0.000722 mole) of 11 aza-10-deoxo-10-
dihydroerythromycin A in 20 ml CHCl3 were added 0.0589 ml (0.000741 mole)
of formaldehyde (approx. 35% w./w.) and 0.00283 g (0.000735 mole) of
formic acid (approx. 98 to 100% w./w.). The reaction mixture was stirred for
8 hours while heating under reflux, then cooled to ambient temperature,
whereupon were added 15 ml of water (pH 5.8). The pH of the reaction
mixture was adjusted to 5.0 by means of 2 N HCl, whereupon the CHCl3 layer
was separated. To the aqueous part was added 15 ml of CHCl3, the pH of the
reaction suspension was adjusted to 7.5 by means of 20% NaOH, the layers
were separated and subsequently the aqueous layer was extracted three times
with 15 ml of CHCl3. The combined chloroform extracts having pH 7.5 were
dried over K2CO3 and evaporated under reduced pressure, yielding 0.45 g
(82.4%) of N-methyl-11-aza-10-deoxo-10-dihydro erythromycin A
(azithromycin), m.p. 113°-115°C. [α]D
20= - 37.0 (1% in CHCl3).
Brand name
Zithromax (Pfizer);
Zmax (Pfizer);Sunamed.
Therapeutic Function
Antibiotic
Antimicrobial activity
It is less potent than erythromycin A against Gram-positive isolates, but is more active against Gram-negative bacteria. It is four times more potent than erythromycin A against H. influenzae, N. gonorrhoeae and Campylobacter spp., and twice as active against Mor. catarrhalis. It also exhibits superior potency against Enterobacteriaceae, notably Esch. coli, Salmonella enterica serotypes, and Shigella spp. It is active against Mycobacteria, notably the M. avium complex and against intracellular micro-organisms such as Legionella and Chlamydia spp.
Chemical modification at the 9 position of the erythronolide A ring of erythromycin A blocks the internal ketalization and markedly improves acid stability. At pH 2, loss of 10% activity occurred in less than 4 s with erythromycin A, but took 20 min with azithromycin. The AUC at 0–24 h is 4.5 mg.h/L. The level is only slightly increased on repeated dosing.
Binding to plasma protein varies with the concentration, from around 50% at 0.05 mg/L to 7.1% at 1 mg/L. The apparent elimination half-life is dependent upon sampling interval: between 8 and 24 h it ranged from 11 to 14 h; between 24 and 72 h it was 35–40 h.
It rapidly penetrates the tissues, reaching levels that approach or, in some cases, exceed the simultaneous plasma levels and persist for 2–3 days. Only about 6% of the dose is found in urine in the first 24 h.
General Description
The spectrum of antimicrobial activity of azithromycin issimilar to that observed for erythromycin and clarithromycinbut with some interesting differences. In general,it is more active against Gram-negative bacteria and less activeagainst Gram-positive bacteria than its close relatives.The greater activity of azithromycin against H. influenzae,M. catarrhalis, and M. pneumoniae coupled with its extendedhalf-life permits a 5-day dosing schedule for thetreatment of respiratory tract infections caused by thesepathogens. The clinical efficacy of azithromycin in the treatmentof urogenital and other sexually transmitted infectionscaused by Chlamydia trachomatis, N. gonorrhoeae, H.ducreyi, and Ureaplasma urealyticum suggests that singledosetherapy with it for uncomplicated urethritis or cervicitismay have advantages over use of other antibiotics.
Pharmaceutical Applications
A semisynthetic derivative of erythromycin A, supplied as the dihydrate for oral administration.
Biological Activity
Macrolide antibiotic. Inhibits 50S ribosomal subunit formation and elongation at transpeptidation step in gram-positive and gram-negative organisms. Orally active with improved pharmacokinetics over erythromycin in mouse models.
Clinical Use
Azithromycin is commonly the first choice for treatment of infections that require a macrolide.
Veterinary Drugs and Treatments
Azithromycin with its relative broad spectrum and favorable pharmacokinetic
profile may be useful for a variety of infections in
veterinary species. Little data is published at this time, however.
Azithromycin has been shown to be ineffective in the treatment of
Mycoplasma haemofelis in cats.
Azithromycin may be potentially useful for treating Rhodococcus
infections in foals.
Drug interactions
Potentially hazardous interactions with other drugs
Anti-arrhythmics: increased toxicity with
disopyramide; increased risk of ventricular
arrhythmias with dronedarone - avoid.
Antibacterials: possibly increased rifabutin
concentration (increased risk of uveitis and
neutropenia) - reduce dose of rifabutin.
Anticoagulants: effect of coumarins may be enhanced.
Antidepressants: the manufacturer of reboxetine
advises to avoid concomitant use.
Antihistamines: may inhibit the metabolism of
mizolastine (risk of hazardous arrhythmias) - avoid.
Antimalarials: avoid with artemether/lumefantrine;
increased risk of ventricular arrhythmias with
piperaquine with artenimol - avoid.
Antipsychotics: increased risk of ventricular
arrhythmias with droperidol - avoid.
Antivirals: concentration possibly increased by ritonavir.
Ciclosporin: may inhibit the metabolism of
ciclosporin (increased ciclosporin levels).
Colchicine: treatment with both agents has been
shown in a study to increase the risk of fatal
colchicine toxicity, especially in patients with renal
impairment - avoid.
Ergot alkaloids: increased risk of ergotism - avoid.
Statins: possible increased risk of myopathy with
atorvastatin and simvastatin.
Metabolism
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. Azithromycin is excreted in bile mainly as
unchanged drug. Ten metabolites have also been detected in
bile, which are formed through N- and O- demethylation
in the liver, hydroxylation of desosamine - and aglycone
rings and cleavage of cladinose conjugate. The metabolites
of azithromycin are not microbiologically active
Mode of action
Azithromycin reversibly binds to the 50S ribosomal subunit of the 70S ribosome of sensitive microorganisms, thereby inhibiting the translocation step of protein synthesis, wherein a newly synthesized peptidyl tRNA molecule moves from the acceptor site on the ribosome to the peptidyl (donor) site, and consequently inhibiting RNA-dependent protein synthesis leading to cell growth inhibition and cell death.
