Comparative Tolerability of Intravenous Azithromycin, Clarithromycin and Erythromycin in Healthy Volunteers: Results of a Double-Blind, Double-Dummy, Four-Way Crossover Study

Torsten Zimmermann, Heinrich Laufen, Klaus-Dieter Riedel, Pfizer Research and Development, Illertissen, Germany; Glenda Treadway, Pfizer Pharmaceutical Group, Pfizer Inc., New York, USA; Alexander Wildfeuer, Pfizer Research and Development, Illertissen, Germany

Clin Drug Invest. 2001;21(8) 

In This Article

Abstract and Introduction

Objective: To compare the tolerability of intravenous azithromycin, clarithromycin, erythromycin and placebo.
Design: A double-blind, double-dummy, placebo-controlled, four-way crossover study was conducted in 12 healthy male volunteers. The participants were randomised to receive 1-hour intravenous infusions of azithromycin 500mg (2 mg/ml) once daily, erythromycin 500mg (1 mg/ml) three times daily, clarithromycin 500mg (2 mg/ml) twice daily, or placebo (normal saline, 500ml) three times daily, with each regimen administered for 3 days. There was a minimum 4-week washout period before participants switched to an alternative regimen, in random sequence, until all four regimens had been completed. Participants were monitored for infusion site reactions and gastrointestinal (GI) adverse events.
Results: Clarithromycin caused clinically significant infusion site pain in 92% of the 12 participants evaluated and was exclusively associated with phlebitis and inflammation. Areas under score-time curves (AUSs) rating the intensity of inflammation and pain were significantly higher for clarithromycin compared with azithromycin (p < 0.0005). Erythromycin infusion caused clinically significant abdominal pain or nausea in 25% of participants. The AUSs for GI tolerability were significantly different for erythromycin compared with azithromycin (p < 0.001). Discontinuation rates due to infusion site reactions were 0% for azithromycin, 50% for clarithromycin, and 8% each for erythromycin and placebo. Treatment with erythromycin was interrupted or discontinued as a result of abdominal pain in 17% of patients and as a result of nausea in 8% of patients.
Conclusions: Intravenous azithromycin had better infusion site tolerability than clarithromycin and better GI tolerability than erythromycin. The superior tolerability of azithromycin may avoid the discontinuation of intravenous antimicrobial therapy in seriously ill patients and assist in reducing the duration of hospitalisation and the cost of patient management.

Macrolide antibacterials possess activity against a wide range of bacterial pathogens. Erythromycin, the first macrolide to be developed, is effective against Streptococcus pneumoniae, Mycoplasma pneumoniae, Legionella pneumophila and Chlamydia trachomatis.[1] The newer macrolides -- such as clarithromycin, a methoxy derivative of erythromycin -- have extended spectra of activity and have proved effective against HIV-related opportunistic infections, such as Mycobacterium avium complex disease.[1,2,3] Azithromycin is a novel azalide antibacterial that, although structurally related to erythromycin, contains a methyl-substituted nitrogen at position 9Ain the macrolide ring.[4] Its activity not only encompasses that of erythromycin and the newer macrolides, but also extends to Gram-negative organisms, including Haemophilus influenzae and Moraxella catarrhalis. In addition, it is active against Chlamydia pneumoniae and Staphylococcus aureus. Azithromycin is indicated for the treatment of community acquired pneumonia due to these pathogens, as well as S. pneumoniae, M. pneumoniae and L. pneumophila.[1] Not only does azithromycin have a more extensive spectrum of activity, it also differs from other macrolides because of its longer elimination half-life and superior tissue penetration, allowing once-daily administration.[5]

For certain patients who cannot take oral medications, or who may have severe infections, initial intravenous treatment may be necessary. An intravenous formulation of erythromycin has been available and in clinical use for many years. However, its usefulness can be limited by a high incidence of adverse gastrointestinal (GI) effects.[6] This is probably due to prokinetic effects mediated by motilin receptors.[7] In addition, phlebitis can occur when intravenous erythromycin is administered at high concentrations.[8]

Until recently, the only alternative intravenous macrolide therapy has been clarithromycin. However, the availability of intravenous clarithromycin is relatively limited: the formulation is approved only in the UK and certain other European countries, and is not licensed in the USA. The development of an intravenous formulation of clarithromycin was regarded as a major therapeutic advance because the incidence of GI intolerance proved markedly less than with erythromycin.[9] However, reports indicate that the local tolerability of intravenous clarithromycin is no better than that of erythromycin.[10,11]

The newest option for parenteral macrolide therapy is azithromycin, which, in two non-comparative studies, was shown to have a favourable local and GI tolerability profile.[12,13] In the USA, intravenous azithromycin is approved for the treatment of community-acquired pneumonia and pelvic inflammatory disease in adults who require initial intravenous therapy.[14]

The present study, conducted in healthy volunteers, was designed to provide comparative data about the tolerability of azithromycin, clarithromycin and erythromycin when administered intravenously in a double-blind manner at doses and concentrations corresponding to standard therapy.

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