, Volume 51, Issue 3, pp 483-505
Date: 31 Oct 2012

Azithromycin

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Abstract

Synopsis

The azalide antibacterial agent azithromycin is a semisynthetic acid-stable erythromycin derivative with an expanded spectrum of activity and improved tissue pharmacokinetic characteristics relative to erythromycin. The drug is noted for its activity against some Gram-negative organisms associated with respiratory tract infections, particularly Haemophilus influenzae. Azithromycin has similar activity to other macrolides against Streptococcus pneumoniae and Moraxella catarrhalis, and is active against atypical pathogens such as Legionella pneumophila, Chlamydia pneumoniae and Mycoplasma pneumoniae.

Once-daily administration of azithromycin is made possible by the long elimination half-life of the drug from tissue. Azithromycin is rapidly and highly concentrated in a number of cell types after absorption, including leucocytes, monocytes and macrophages. It undergoes extensive distribution into tissue, from where it is subsequently eliminated slowly.

A 3-day oral regimen of once-daily azithromycin has been shown to be as effective as 5- to 10-day courses of other more frequently administered antibacterial agents [such as erythromycin, amoxicillin-clavulanic acid and Phenoxymethylpenicillin (penicillin V)] in patients with acute exacerbations of chronic bronchitis, pneumonia, sinusitis, pharyngitis, tonsillitis and otitis media. Adverse effects of azithromycin are mainly gastrointestinal in nature and occur less frequently than with erythromycin.

Azithromycin is likely to prove most useful as a 3-day regimen in the empirical management of respiratory tract infections in the community. Its ease of administration and 3-day duration of therapy, together with its good gastrointestinal tolerability, should optimise patient compliance (the highest level of which is achieved with once-daily regimens). Azithromycin is also likely to be useful in the hospital setting, particularly for outpatients and for those unable to tolerate erythromycin.

Overview of in Vitro Antibacterial Activity

Azithromycin has a similar spectrum of activity to erythromycin but is particularly noted for its activity against a number of Gram-negative organisms. On the basis of in vitro data, azithromycin is more active than erythromycin, clarithromycin and roxithromycin against Haemophilus influenzae. Azithromycin shows similar activity to erythromycin, clarithromycin and roxithromycin against Moraxella catarrhalis (with good activity against β-lactamase-positive strains of this organism) and Streptococcus pneumoniae.

Clinical isolates of Legionella pneumophila and Chlamydia pneumoniae are susceptible to azithromycin. In particular, the drug is very active against Mycoplasma pneumoniae, with in vitro data from 1 study showing the mean minimum drug concentration required to inhibit 90% of strains (MIC90) for erythromycin, clarithromycin and roxithromycin to be at least 32.5 times greater than that for azithromycin.

Erythromycin-susceptible strains of Staphylococcus aureus and most streptococci are susceptible to azithromycin, and the drug has shown good activity against S. pyogenes in studies conducted in vitro. Streptococcal and staphylococcal species that are resistant to erythromycin are also likely to be resistant to azithromycin, as are methicillin-resistant strains of S. aureus.

Overview of Pharmacokinetic Properties

Oral administration of azithromycin 500mg produces a peak serum concentration of approximately 0.4 to 0.45 mg/L after 2.5 hours. The drug is rapidly and highly concentrated in white blood cells and macrophages, undergoes extensive tissue distribution and achieves high concentrations in pulmonary and tonsillar tissue.

Azithromycin is largely eliminated unchanged via the faecal route, although some hepatic metabolism does occur. Polyphasic elimination reflects the initial rapid distribution of the drug into tissue and its subsequent slow elimination therefrom. A mean terminal serum elimination half-life of 57 hours has been reported for azithromycin.

Therapeutic Efficacy of 3-Day Azithromycin in Respiratory Tract Infections

Results of comparative trials have shown similar clinical efficacy for 3-day regimens of azithromycin and 5- to 10-day courses of other antibacterial drugs, including amoxicillin-clavulanic acid, erythromycin, clarithromycin, roxithromycin and josamycin in patients with acute bronchitis, acute exacerbations of chronic bronchitis or pneumonia. Combined rates of clinical cure and clinical improvement (cure plus improvement) 10 to 14 days after the start of therapy were similar for azithromycin and amoxicillin-clavulanic acid in patients with infections caused mainly by S. pneumoniae, H. influenzae or M. catarrhalis. Bacteriological efficacy (based on the eradication or presumed eradication of infecting pathogens) varied between trials but was similar for azithromycin and the comparator agent in most studies.

Azithromycin administered once a day for 3 days was as effective as a 5-day regimen of the drug in 84 patients with pneumonia caused by atypical pathogens such as M. pneumoniae, C. psittaci or Coxiella burnetii. Most studies in lower respiratory tract infections involved adults, but some paediatric data are also available.

Clinical cure plus improvement rates of 93 to 100% were reported in studies of patients (including children) with upper respiratory tract infections (acute pharyngitis, tonsillitis, sinusitis or otitis media) who received 3-day courses of azithromycin. Similar cure plus improvement rates were observed after 7- to 10-day courses of erythromycin, clarithromycin, roxithromycin, Phenoxymethylpenicillin (penicillin V), amoxicillin (with or without clavulanic acid) and cefaclor in these trials.

Tolerability

Pooled tolerability data from phase II and III studies of 3995 patients aged from 2 to 94 years showed orally administered azithromycin to be associated predominantly with gastrointestinal and central and peripheral nervous system adverse events (most of the patients who were included had received a total dose of azithromycin 1500mg over 5 days). The gastrointestinal tolerability of azithromycin was superior to that of erythromycin in this analysis.

A further analysis of tolerability data from clinical trials which involved 1129 children and young adults, 606 of whom received azithromycin (544 received the 3-day regimen), showed an incidence of adverse events of 7.6% for azithromycin and 13.8% overall for other antibacterial drugs, including amoxicillin, Phenoxymethylpenicillin, erythromycin and flucloxacillin. Gastrointestinal adverse events were reported significantly less frequently by azithromycin recipients than by those receiving other drugs.

Pooled data from 43 studies in 4499 children (aged 6 months to 16 years) who received 3-day azithromycin showed similar overall tolerability for azithromycin and a number of penicillins, cephalosporins and macrolides.

Azithromycin has not been associated with any clinically significant biochemical or haematological abnormalities.

Drug Interactions

Azithromycin does not interact with the hepatic cytochrome P450 system and is not associated with the pharmacokinetic drug interactions seen with erythromycin and other macrolides. The drug does not appear to affect metabolism of theophylline, carbamazepine, midazolam or terfenadine. Furthermore, the anticoagulant effect of a single 15mg dose of warfarin was not affected by concurrent therapy with azithromycin.

Serum cyclosporin and digoxin concentrations should be monitored when either of these 2 agents is given during treatment with azithromycin. Concurrent administration of the drug with ergot derivatives should be avoided.

Dosage and Administration

An oral dose of azithromycin 500mg should be given once daily for 3 days in upper and lower respiratory tract infections. Children aged over 6 months who weigh less than 45kg should receive 10 mg/kg once daily for 3 days. No dosage recommendations have been made for children aged under 6 months. Although it is recommended that azithromycin capsules are taken 1 hour before or 2 hours after food, recent data indicate that this is not necessary with the oral suspension and a novel tablet formulation of the drug.

Various sections of the manuscript reviewed by: A.L. Barry, Clinical Microbiology Institute, Tualatin, Oregon, USA; A. Bauernfeind, Max von Pettenkofer-Institut, Ludwig-Maximilians Universität München, Munich, Germany; E. Bergogne-Bérézin, Service de Microbiologie, CHU Bichat-Claude Bernard, Paris, France; M.A. Cooper, Department of Microbiology, Russells Hall Hospital, Dudley, West Midlands, England; B.J. Guglielmo, Division of Clinical Pharmacy, Department of Pharmaceutical Sciences, University of California, San Francisco, California, USA; I.M. Hoepelman, Department of Internal Medicine, Section of Clinical Immunology and Infectious Diseases, University Hospital, Utrecht, The Netherlands; D.L. Morris, Department of Surgery, St George Hospital, University of New South Wales, Kogarah, New South Wales, Australia; M.E. Pichichero, Department of Microbiology and Immunology, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New York, USA.