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


During this study, clarithromycin and azithromycin were given at the dosages and concentrations recommended by their respective manufacturers. The dosage of erythromycin used in clinical practice is very variable and depends on disease severity. The usual intravenous dosage in adults and paediatric patients is in the range 30 to 50 mg/kg/day, given in divided doses at 6- or 8-hour intervals. However, higher doses of 1000mg may be given up to four times daily in severely ill patients, such as in those with Legionnaires' disease.[17] The concentration of the solution of erythromycin lactobionate can also vary between 1 and 5 mg/ml. The concentration use din the present study was low, but is within the recommended range. High concentrations of erythromycin may be acceptable, or even advantageous, in severely ill, mechanically ventilated patients because of stimulation of gastric emptying,[18] but the resultant GI discomfort associated with high-concentration erythromycin infusion would be likely to prove unacceptable to a healthy volunteer.

The tolerability of intravenous azithromycin and clarithromycin clearly differentiates between the two antimicrobial agents with respect to local effects. The clinical adverse event profile and the VAS evaluations consistently showed that clarithromycin had poorer local tolerability than either azithromycin or erythromycin. The clinical evidence was supported by statistical analysis. The severe pain associated with inflammation or phlebitis forced discontinuation of the clarithromycin infusion in 50% of participants, most of whom required anti-inflammatory treatment thereafter. Such poor tolerability might only be acceptable in limited clinical situations (i.e. if no alternatives were available).

The finding is not unexpected: inferior local tolerability of clarithromycin compared with erythromycin has been previously described.[8,9] Furthermore, local intolerance of intravenous clarithromycin was observed in early (Phase I) clinical trials, and there have been reports of high incidences of phlebitis in patients when receiving intravenous clarithromycin for the treatment of community-acquired pneumonia.[8,9,19] In an attempt to overcome the problem and reduce the likelihood of pain, formulation additives (e.g. bile salt-phospholipid mixtures) or a liposomal formulation were evaluated in preclinical tests, but without success.[20]

The severity of local inflammation associated with intravenous administration of erythromycin is influenced by the amount and concentration of drug administered.[21] Infusion of 1g intravenous doses is often followed by thrombophlebitis,[22,23] but slow rates of infusion can help to minimise the inflammatory response.[6] GI disturbances after oral erythromycin are a widely acknowledged drawback, and they also occur after intravenous administration.[21,23] Rate of infusion and plasma erythromycin concentration also correlate with nausea and stomach discomfort.[6] Sometimes, such complaints are sufficiently severe in intensity to necessitate cessation of therapy.[24]

The design of the present study acknowledged the fact that high-concentration erythromycin infusion can result in phlebitis.[8] By using a lower concentration, although still within the recommended range, the local tolerability of erythromycin proved acceptable compared with clarithromycin. However, we noted that, even if local reactions could be minimised, GI events remained a problem: at least 25% of participants experienced clinically significant GI complaints while receiving erythromycin, with most complaints occurring on the second day of administration. This represents the poorest GI tolerability of any agent in this study.

The relatively high incidence of local adverse events, at the site where no active drug was infused, observed in the present study was possibly due to the fact that identical venous sites had to be punctured repeatedly during the course of medication, and eventually smaller veins had to be chosen. Under normal clinical circumstances, a catheter would not be removed, but for the convenience of the volunteers, daily removal was considered appropriate in this study.

The 2 mg/ml solution of azithromycin evaluated in this study was well tolerated, both in terms of local reactions and GI events, and there were no medication discontinuations in participants while receiving azithromycin infusions. Subjective and objective ratings of inflammatory signs at the end of medication administration were not significantly different from ratings for placebo, and thus consistently underlined the clinical observations of only a few local adverse events. Possibly, the azalide azithromycin, which differs structurally from the prototype macrolides,[4] does not interact with nerve endings within the venous wall, nor does significant precipitation of drug seem to occur at the site of injection (Pfizer Inc., data on file). The excellent local tolerability of intravenous azithromycin combined with the need to administer the drug only once daily, as opposed to multiple daily drug administration, which was associated with the more frequent occurrence of adverse events in this study, may contribute to an increased probability that an intravenous course of treatment will be completed.

The present azithromycin results are consistent with previous observations. In early Phase I studies, once-daily infusions of azithromycin 2g for 10 days, using concentrations of up to 2.5 mg/ml, were well tolerated (Pfizer Inc., data on file). In single-dose intravenous studies in healthy volunteers, azithromycin doses of up to 4g infused over 2 hours were also well tolerated.[12]

The inclusion of a statistical power calculation in this study was not possible; insufficient data were available about the variability of the primary parameters. Hence, the study size was chosen on the basis of practicality rather than biometric factors. Although the study population was small, the statistical evaluation was enhanced by both inter-and intrapatient data analysis. As a result, this first study of the relative tolerability of the intravenous formulations of azithromycin, erythromycin and clarithromycin compared with placebo yielded observations relevant to the clinical setting.


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