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Azithromycin Extended Release

A Review of its Use in the Treatment of Acute Bacterial Sinusitis and Community-Acquired Pneumonia in the US

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Summary

Abstract

Azithromycin is a macrolide antibacterial agent. The novel microspheres oral extended-release formulation (Zmax™) is the first antibacterial drug approved in the US for administration as a single dose in adult patients with mild to moderate acute bacterial sinusitis (ABS) or community-acquired pneumonia (CAP). It has a broad spectrum of in vitro antibacterial activity against Gram-positive, Gram-negative and atypical pathogens that cause ABS and CAP infections (including Streptococcus pneumoniae), and achieves good tissue penetration. Azithromycin extended release is an effective and generally well tolerated treatment in patients with ABS or CAP. The clinical cure rates of a single 2.0g dose of azithromycin extended release were noninferior to those obtained with a 10-day regimen of levofloxacin in patients with ABS, and with 7-day regimens of clarithromycin extended release or levofloxacin in patients with CAP. With a pharmacodynamic and pharmacokinetic profile well suited to administration as a single-dose regimen that may offer the advantage of improved compliance and convenience compared with once-daily longer-course regimens, azithromycin extended release is a new option in the empirical treatment of adult patients with mild or moderate ABS or CAP in the US.

Pharmacological Properties

Azithromycin inhibits microbial protein synthesis. In North American surveillance studies, azithromycin showed variable in vitro bacteriostatic activity against clinical isolates of S. pneumoniae and good activity against those of Haemophilus influenzae and Moraxella catarrhalis. Azithromycin also demonstrated good activity against selected strains and/or clinical isolates of Chlamydophila pneumoniae and Mycoplasma pneumoniae. In time-kill studies azithromycin demonstrated bactericidal activity against selected strains and/or clinical isolates of M. catarrahlis, S. pneumoniae and H. influenzae, and a prolonged post-antibiotic effect against the latter two pathogens.

Recent surveillance studies indicate that rates of resistance to azithromycin are similar to those of other macrolides in clinical isolates of S. pneumoniae (≈28–30%) and have been stable in recent years. There was a high level of co-resistance between penicillin- and azithromycin-resistant S. pneumoniae isolates. However, susceptibility of clinical isolates of H. influenzae to azithromycin is generally very high (≈99%).

In animal models of S. pneumoniae infection, the pharmacokinetic/pharmacodynamic parameter best predictive of azithromycin clinical efficacy was the area under the concentration-time curve from time zero to 24 hours to minimum drug inhibitory concentration ratio (AUC24: MIC ratio), and the curative effect of oral azithromycin administered as a single dose or a simulated extended-release dose was generally superior to that of once-daily 2- to 5-day regimens of the drug.

The microsphere extended-release formulation of azithromycin is a powder reconstituted with water for oral administration as a single 2.0g dose. Sustained release of the drug is achieved via diffusion from the microspheres, with the majority of the administered dose released in the lower gastrointestinal tract. Time to peak serum concentration is 5 hours. Azithromycin extended release is well absorbed; the mean maximum serum concentration is 0.82 µg/mL and the AUC24 is about 8.62 µg · h/mL. Absorption of azithromycin extended release 2.0g was greater in the fed than in the fasted state; thus, azithromycin extended release should be taken on an empty stomach to ensure slower absorption. Azithromycin is excreted predominantly as unchanged drug in the faeces. The terminal elimination half-life of azithromycin extended release is 59 hours.

A single 2.0g dose of azithromycin extended release is not pharmacokinetically bioequivalent to, or interchangeable with, the immediate-release oral formulations (tablets or powder for oral suspension) of azithromycin. Azithromycin extended release achieves higher intracellular concentrations in mononuclear and polymorphonuclear leukocyte and alveolar cells, and higher tissue/fluid concentrations in lung serum, lung tissue and lung epithelial lining fluid than in serum. Moreover, azithromycin concentrations in these compartments were generally greater than those achieved with the immediate-release formulation.

Therapeutic Use

In three phase III non-inferiority trials (n = 427–538), a single 2.0g dose of oral azithromycin extended release was no less effective in producing a clinical cure at the test of cure visit (primary efficacy endpoint) in adult patients with ABS than a 10-day regimen of oral levofloxacin 500mg once daily, or in adult patients with mild to moderate CAP than 7-day regimens of oral levofloxacin 500mg once daily or oral clarithromycin extended release 1.0g once daily.

Azithromycin extended release and comparator antibacterial agents all demonstrated clinical efficacy against the most common causative pathogens isolated from patients at baseline, including S. pneumoniae, H. influenzae and M. catarrhalis. In the trials in patients with CAP, 91–92% of patients receiving azithromycin extended release, levofloxacin or clarithromycin extended release experienced a bacteriological response (presumed or assessed via eradication).

Tolerability

A single 2.0g dose of azithromycin extended release was generally well tolerated in adult patients with ABS or mild to moderate CAP, with the majority of adverse events being of mild to moderate severity. The most frequent treatment-related adverse event was diarrhoea/loose stools. In trials in patients with CAP, the incidence of treatment-related adverse events in patients receiving azithromycin extended release was significantly higher than in those receiving levofloxacin, but did not differ from that in recipients of clarithromycin extended release. Serious adverse events and rates of discontinuation from treatment because of an adverse event were infrequent with azithromycin extended release or comparator agents.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Authors and Affiliations

  1. Wolters Kluwer Health / Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland, 1311, New Zealand

    Tracy Swainston Harrison & Susan J. Keam

  2. Wolters Kluwer Health, Conshohocken, Pennsylvania, USA

    Tracy Swainston Harrison & Susan J. Keam

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Correspondence to Susan J. Keam.

Additional information

Various sections of the manuscript reviewed by: M.C. De Salvo, Hospital Enrique Tornú, Buenos Aires, Argentina; H. Lode, Krankenhaus Zehlendorf/Heckeshorn, Freie Universitat Berlin, Berlin, Germany; M.N. Lutfiyya, Department of Family and Community Medicine, University of Illinois College of Medicine at Rockford, Rockford, Illinois, USA; A.P. MacGowan, Department of Microbiology, Southmead Health Services NHS Trust, Bristol Centre for Antimicrobial Research and Evaluation, Bristol, England; C.E. Nord, Karolinska Institute, Division of Clinical Bacteriology, Hudding University Hospital, Stockholm, Sweden; V. Snow, Clinical Programs and Quality of Care, American College of Physicians, Philadelphia, Pennsylvania, USA.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘azithromycin’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE, EMBASE and Adisbase search terms were ‘azithromycin’ and ‘microspheres’. Searches were last updated 9 February 2007.

Selection: Studies in patients with acute bacterial sinusitis or community-acquired pneumonia who received azithromycin microspheres. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Azithromycin microspheres, antibacterials, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

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Harrison, T.S., Keam, S.J. Azithromycin Extended Release. Drugs 67, 773–792 (2007). https://doi.org/10.2165/00003495-200767050-00010

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  • DOI: https://doi.org/10.2165/00003495-200767050-00010

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