a Department of Epidemiology, University of Washington, Seattle b Department of Medicine, University of Washington, Seattle c Department of Pathobiology, University of Washington, Seattle d The Heart Institute, Spokane, Washington, USA
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Abstract |
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Introduction |
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Although the one published cardiovascular clinical trial evaluating the use of azithromycin1 employed a maximum dose of a total of 3.0 g the optimal course of azithromycin treatment directed against C. pneumoniae for the primary or secondary prevention of cardiac disease is likely to be significantly longer in duration, with a correspondingly higher cumulative dose. Experience to date with longer courses of azithromycin is limited primarily to prophylaxis of Mycobacterium avium infection among AIDS patients.3 Among this group of very ill patients prolonged weekly administration of azithromycin has been well tolerated. However, this experience cannot be readily generalized to other patient groups.
The azithromcyin study also reported an effect of treatment on anti-C. pneumoniae antibody titre, with a significantly larger proportion of the azithromycin group demonstrating a decrease in IgG titre compared with an untreated group.1 However, another study of adults with coronary artery disease, in which patients were randomized to 4 months of treatment with 100 mg/day of doxycycline or placebo, found no effect of treatment on antibody titre.4
To obtain data on longer courses of azithromycin among patients with cardiovascular disease, we conducted a pilot study of safety and effect on anti-C. pneumoniae antibody titre of azithromycin treatment following percutaneous coronary revascularization procedures.
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Materials and methods |
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Eligible consenting subjects were randomized 1:1 in a double-blind fashion to azithromycin (500 mg on days one and two, then 250 mg on days three to 28 (total dose 8 g)) or placebo. Participants were contacted by telephone at 2 weeks and 4 weeks after enrolment to assess adverse events and compliance with treatment.
Serum samples were obtained for testing for anti-C. pneumoniae IgM, IgG and IgA titres by the microimmunofluorescence test at enrolment on most subjects and at 6 months after enrolment on a subset of patients. Titres are expressed as reciprocals of the serum dilution.
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Results |
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Eight subjects did not complete the 30-day treatment period. Symptoms leading to discontinuation of treatment included stomach pain (one azithromycin and one placebo recipient), vaginal Candida infection (one placebo recipient) and diarrhoea (one azithromycin recipient). The latter participant developed diarrhoea 3 weeks after enrolment and was instructed to stop the study drug on day 26. The patient had a chronic anal fissure and haemorrhoids, which may have been exacerbated by the diarrhoea and underwent outpatient surgical repair 6 weeks after enrolment. Four subjects (two azithromycin and two placebo) discontinued treatment for reasons unrelated to adverse events.
Azithromycin recipients were no more likely than placebo recipients to report adverse events during the 30-day treatment period (Table I). Symptoms of decreased auditory acuity or tinnitus were not specifically solicited. However, none of the subjects reported the occurrence of either symptom during the follow-up telephone calls.
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Discussion |
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At very high doses azithromycin has been associated with ototoxicity.6 Four patients with HIV infection treated for M. avium infection for an average of 7.6 weeks at a dosage of azithromycin of 600 mg/day (total dose 32 g) had documented sensorineural hearing loss in one report.7 Hearing loss has also been reported in non-HIV infected elderly patients treated for mycobacterial infection with a dosage of 600 mg/day.8 We did not detect any evidence of ototoxicity at the dose used in our study, although our ability to detect uncommon adverse events was limited by our relatively small sample size.
In sero-epidemiological studies, sero-positivity to C. pneumoniae has been
associated with an increased risk of cardiovascular outcomes.9,10 There is therefore interest in determining
whether the serological titre can be used as a marker of response to therapy in cardiovascular
clinical trials of antibiotic therapy directed against C. pneumoniae. In one reported
clinical trial, patients with stable coronary artery disease who had baseline C. pneumoniae IgG titres 64 were assigned to treatment with one or two 3-day courses of 500 mg
azithromycin or placebo.1 At 6 months, 43% (17/40) of the
azithromycin group had a decrease in IgG titre to
16 compared with 10% (2/20) of the
placebo group (P = 0.02), suggesting an effect of azithromycin on anti-C.
pneumoniae antibody titre. In another study, however, men who were post-coronary artery
bypass surgery were randomized to 4 months of 100 mg/day of doxycycline or placebo.3 At 6 months, a change in either IgG or IgA titre from
baseline was found in only one of 16 doxycycline- and three of 17 placebo-treated patients,
indicating no significant effect of treatment on anti-C. pneumoniae antibody titre.
We found very little change in either IgG or IgA antibody titre between baseline and 6 month follow-up in either the azithromycin or placebo groups and no significant difference in the proportion of subjects with a change in titre between those two groups. This suggests that anti-C. pneumoniae antibody titre is unlikely to be a useful marker of response to azithromycin therapy in the conduct of cardiovascular clinical trials.
Safety is a primary concern in the design of clinical trials of investigational therapies. The results of this pilot study provide no evidence that the course of azithromycin therapy used is associated with an unacceptable adverse event profile. While future clinical trials must incorporate careful monitoring for adverse events, these data should be useful in making decisions regarding the optimal dose and duration of treatment to be evaluated in these studies.
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Acknowledgments |
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Notes |
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References |
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2 . Gurginkel, E., Bozovich, G., Daroca, A., Beck, E. & Mautner, B. (1997). Randomised trial of roxithromycin in non-Q-wave coronary syndromes: ROXIS pilot study. ROXIS Study Group. Lancet 350, 4047.[ISI][Medline]
3
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Havlir, D. V., Dube, M. P., Sattler, F. R., Forthal, D. N.,
Kemper, C. A., Dunne, M. W. et al. (1996). Prophylaxis against
disseminated Mycobacterium avium complex with weekly azithromycin, daily rifabutin,
or both. California Celloborative Treatment Group. New England Journal of Medicine 335, 3928.
4 . Sinisalo, J., Mattila, K., Nieminen, M. S., Valtonen, V., Syrjälä, M., Sundberg, S. et al. (1998). The effect of prolonged doxycycline therapy on Chlamydia pneumoniae production. Journal of Antimicrobial Chemotherapy 41, 8592.[Abstract]
5 . Hopkins, S. (1991). Clinical toleration and safety of azithromycin. American Journal of Medicine 91, Suppl. 3A, 40S5.
6 . Wallace, M. R., Miller, L. K., Nguyen, M. T. & Shields, A. R. (1994). Ototoxicity with azithromycin. Lancet 343, 241.
7 . Tseng, A. L., Dolovich, L. & Salit, I. E. (1997). Azithromycin-related ototoxicity in patients infected with human immunodeficiency virus. Clinical Infectious Diseases 24, 767.[ISI][Medline]
8 . Brown, B. A., Griffith, D. E., Girard, W., Levin, J. & Wallace, R. J. (1997). Relationship of adverse events to serum drug levels in patients receiving high-dose azithromycin for mycobacterial lung disease. Clinical Infectious Diseases 24, 95864.[ISI][Medline]
9 . Saikku, P., Leinonen, M., Tenkanen, L., Linnanmaki, E., Ekman, M. R., Manninen, V. et al. (1992). Chronic Chlamydia pneumoniae infection as a risk factor for coronary heart disease in the Helsinki Heart Study. Annals of Internal Medicine 116, 2738.[ISI][Medline]
10 . Thom, D. H., Grayston, J. T., Siscovick, D. S., Wang, S.-P., Weiss, N. S. & Daling, J. R. (1992). Association of prior infection with Chlamydia pneumoniae and angiographically demonstrated coronary artery disease. Journal of the American Medical Association 268, 6872.[Abstract]
Received 30 June 1998; returned 28 October 1998; revised 7 November 1998; accepted 21 February 1999