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


The mean age of the 12 study participants was 34 years (range 23 to 45 years), mean bodyweight was 81kg (72 to 110kg), and mean height was 182cm (171 to 198cm). A total of 864 infusions, 216 of which contained active drug, were scheduled according to the protocol; 769 infusions were completed as scheduled. A total of 95 infusions, 52 of which contained active drug, were not performed or not completely administered for medical reasons. Occasionally, infusion was not performed because of difficulties in placing the catheter repeatedly during the course of medication; however, in the majority of instances the infusion was not performed for reasons related to study medication. Of the azithromycin, clarithromycin, erythromycin and placebo infusions, 0%, 13%, 35% and 3%, respectively, could not be performed or were not completely administered for medication related reasons. Analysis was performed on the intention-to-treat principle.

The most common infusion site reaction was local irritation (table I). Phlebitis occurred exclusively in participants when receiving clarithromycin, which was statistically inferior to azithromycin (p < 0.05), but there were no significant differences regarding phlebitis, inflammation, irritation and pain between azithromycin and either erythromycin or placebo. Inflammation was significantly more frequent in participants when given clarithromycin compared with azithromycin (p < 0.005). Phlebitis and/or inflammation occurred in 11/12 (92%) individuals while receiving clarithromycin. All 12 participants when given clarithromycin experienced pain on infusion, and in 11 (92%) individuals the pain was described as being at least moderate in intensity. By comparison, pain was present in 58% of participants during azithromycin treatment (17% of participants had at least moderate pain, but this did not result in discontinuation of infusions). Painful erythromycin infusions were experienced by 25% of participants, and in 8% the intensity of pain was at least moderate. When participants received placebo, 8% reported pain, which in all instances was mild in intensity.

For comparison, infusion site adverse events at the site complementary to where the active drug was infused are also listed in table I. No phlebitis was recorded, but the overall frequency of irritation was 50%, and inflammation occurred with a frequency of about 8%. In general, participants experienced little or no pain.

GI complaints of clinical relevance included abdominal pain or cramps, flatulence and nausea. Abdominal pain was more prominent than nausea (table I), occasionally being accompanied by reports of nausea, meteorism or urgency to defaecate. GI complaints were most frequent when erythromycin was infused, with the occurrence of abdominal pain/cramp in 75% of participants and nausea in 58%. By comparison, abdominal pain/cramp and nausea were only experienced by 25% and 8% of the participants, respectively, when given azithromycin, and by 8% and 8%, respectively, following placebo infusion. The frequency of nausea was significantly higher when erythromycin rather than azithromycin was infused (p < 0.05), but there were no significant differences between azithromycin and either clarithromycin or placebo. In three participants, erythromycin related GI adverse events necessitated deviations from the scheduled drug administration.

Other events of clinical significance were marked elevation of serum transaminases in one participant following erythromycin administration, and a bitter taste was reported in two participants during, and on completion of, clarithromycin infusion. The duration of the taste disturbance was not monitored.

The results obtained from the participants' VAS ratings, including the time course, significance of medication-related differences and trend evaluations, were highly consistent with the investigators' assessments. In the following results, the investigators' evaluations are presented.

During the first infusion, VAS rating profiles were very similar for azithromycin and clarithromycin, both resulting in mild to moderate pain in about 50% of participants. By comparison, the first erythromycin infusion was mildly painful for 25% of participants, and the first placebo infusion was not painful for any participants. The picture changed during the multiple administrations. Profiles of clarithromycin were substantially worse on the evening of study day 1, and during study days 2 and 3, thus identifying clarithromycin as the medication with the poorest local tolerability. Erythromycin infusions had a distinct tendency to become more painful at the end of the 3-day medication schedule. By contrast, pain profiles for the second and third infusions of azithromycin were widely comparable with the first infusion. Pain associated with placebo infusion was, at worst, only mild.

Although pain was often the most prominent sign, in some instances erythema was present without any further inflammatory signs. Since this was a transient phenomenon, it was judged to be without clinical relevance. Inflammatory signs, such as swelling, erythema and tenderness, often developed with a delay of several hours after infusion, with pain on infusion being the initial symptom. However, there was pain on infusion without further development of inflammation, and vice versa (especially in the placebo group).

The AUS profiles of GI tolerability ratings reflected medication-related differences in the occurrence of GI adverse events (table I). The comparison of AUS values confirmed the poor GI tolerability of erythromycin. The highest ratings (i.e. the lowest tolerability) for erythromycin occurred on study day 2. Differences in AUS0-2 values for abdominal pain ratings between azithromycin and erythromycin for the last infusions of study days 1 to 3 were significant (p < 0.001). Any differences between azithromycin and clarithromycin or between azithromycin and placebo were not significant. GI tolerability AUSs were significantly different between azithromycin and erythromycin (p < 0.0005), but not between azithromycin and either clarithromycin or placebo.

A summary comparison of tolerability is shown in figure 1. Infusion site inflammation was evaluated by the investigators, and GI tolerability was assessed by the study participants according to a rating scale. Only values obtained after the active infusions were included in figure 1.

Tolerability of an intravenous infusion of azithromycin 500mg once daily, clarithromycin 500mg twice daily, erythromycin 500mg three times daily, and placebo three times daily for 3 days in a double-blind, double-dummy, four-way crossover study in 12 healthy volunteers. * Intravenous site reactions were significantly lower with azithromycin compared with clarithromycin (p < 0.05). ** Gastrointestinal adverse reactions were significantly lower with azithromycin compared with erythromycin (p < 0.05).

Kaplan-Meier plots of successful medication completion, showing the time course of dropouts in a double-blind, double-dummy, four-way crossover study of 12 healthy volunteers comparing 3-day intravenous drug administration with: azithromycin 500mg once daily (A); clarithromycin 500mg twice daily (C); erythromycin 500mg three times daily (E) and placebo (P) three times daily. ** Azithromycin was associated with a significantly lower incidence of discontinuations than clarithromycin (p < 0.05).

All 12 participants completed the study as scheduled. The time course of dropouts for medical reasons is depicted in figure 2.

Infusion discontinuation because of pain and inflammation/phlebitis occurred in 50% of participants while receiving clarithromycin. Inflammation, or extravasation with subsequent inflammation, resulted in a discontinuation rate of 8% when individuals received erythromycin. The incidence of discontinuation was also 8% for placebo, and 0% for azithromycin. Most often, phlebitis/inflammation resulted in discontinuation of study medication on study day 3, and required the initiation of anti-inflammatory treatment.

In one participant, erythromycin infusion had to be terminated because of nausea, and in two participants, intermittent discontinuation of erythromycin infusion and treatment with metoclopramide was necessary because of nausea and abdominal pain. Symptoms nearly disappeared on the last day of drug administration, and further drug administration was tolerated.

One participant was withdrawn from erythromycin infusion because of marked elevations in serum transaminase levels after the first day of infusion. Levels returned to normal within the washout period, and he continued to participate in the study.


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