Safety and effect on anti-Chlamydia pneumoniae antibody titres of a 1 month course of daily azithromycin in adults with coronary artery disease

Lisa A. Jacksona,*, Douglas K. Stewartb, San-Pin Wangc , Dennis B. Cooked, Truman Cantrelld and J. Thomas Graystona

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


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A pilot study of azithromycin treatment following percutaneous coronary revascularization procedures was performed to assess safety and the effect of azithromycin treatment on anti-Chlamydia pneumoniae antibody titres. Patients were randomized to a 1 month course of azithromycin (total dose of 8.0 g) or placebo. Safety and compliance were assessed at 2 and 4 weeks and serological testing was performed on samples obtained at enrolment and at 6 months post-enrolment. Azithromycin was well tolerated at this dose. No effect of treatment on antibody titres was demonstrated. These results support further clinical trials to assess the effect of azithromycin treatment on cardiovascular disease outcomes.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Chlamydia pneumoniae has recently been associated with atherosclerotic cardiovascular disease, which has prompted interest in clinical trials to assess the effect of treatment with antibiotics active against C. pneumoniae on cardiovascular outcomes. Two such trials, which evaluated the use of either azithromycin1 or roxithromycin2 in the secondary prevention of cardiac outcomes, have been reported and additional trials are planned or in progress. Azithromycin is particularly well suited for these studies because it is highly active against C. pneumoniae, is well tolerated and is rapidly absorbed and distributed following oral administration, obtaining high intracellular concentrations. Its long half-life also makes it appropriate for less-than-daily dosing schedules.

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.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The study group consisted of patients who had undergone a successful percutaneous coronary revascularization procedure. Eligibility criteria included age 18–79 years; no documented myocardial infarction within 5 days; electrocardiogram-documented QT corrected interval of <0.47; no history of allergy to azithromycin, erythromycin or clarithromycin; and no chronic coumadin treatment or treatment with digitalis, quinidine, theophylline or ergot alkaloids. Patients prescribed a limited course of coumadin following coronary stent placement were eligible for enrolment.

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.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Eighty-eight participants were enrolled and allocated equally to the treatment and placebo arms. Their mean age was 57 years (range 37–79 years) and 74% were male. These characteristics did not differ between treatment groups.

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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Table I. Adverse events reported during the 30-day treatment period by treatment group
 
A serum sample was collected at enrolment from 71 of the 88 subjects, Of those, none had IgM titres >=8, 62 (87%) had IgG titres >=8 and 34 (48%) had IgA titres >=8. Twenty-two of the 71 subjects living close to the enrolment centres were also available for a follow-up serum sample, collected at least 6 months after enrolment (Table II). Twelve exhibited no change in IgG titre between the two samples; two showed a two-fold decrease from baseline to follow-up; and eight showed a two-fold increase from baseline to follow-up. Each of these three groups was evenly divided by study group assignment. Nineteen of the 22 paired specimens showed no change in IgA titre. One of the 11 azithromycin-treated subjects had a 16-fold rise in IgA titre from baseline to follow-up and one had a two-fold decrease. One placebo recipient had a 16-fold decrease in IgA titre between baseline and follow-up.


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Table II. Anti-C. pneumoniae IgA and IgG titres pre- and 6 months post-azithromycin or placebo treatment among adults with coronary artery disease
 

    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
These results indicate that, among this study population, the study dose of azithromycin was well tolerated. The rate of reports of gastrointestinal symptoms among the azithromycin group was similar to that reported for the more standard course of treatment. In reported clinical trials of the 5-day dose, side effects, most commonly gastrointestinal symptoms such as nausea, diarrhoea and abdominal pain, were recorded in approximately 12% of patients.5

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.


    Acknowledgments
 
Azithromycin and placebo were provided by Pfizer, Inc. (Groton, CT, USA).


    Notes
 
* Correspondence address. Box 356236, University of Washington, Seattle, WA 98195-7236, USA. Tel: +1-206-616-7439; Fax: +1-206-543-8525; E-mail: lajack{at}u.washington.edu Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . Gupta, S., Leatham, E. W., Carrington, D., Mendall, M. A., Kaski, J. C. & Camm, A. J. (1997). Elevated Chlamydia pneumoniae antibodies, cardiovascular events, and azithromycin in male survivors of myocardial infarction. Circulation 96, 404–7.[Abstract/Free Full Text]

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, 404–7.[ISI][Medline]

3 . 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, 392–8.[Abstract/Free Full Text]

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, 85–92.[Abstract]

5 . Hopkins, S. (1991). Clinical toleration and safety of azithromycin. American Journal of Medicine 91, Suppl. 3A, 40S–5.

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, 76–7.[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, 958–64.[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, 273–8.[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, 68–72.[Abstract]

Received 30 June 1998; returned 28 October 1998; revised 7 November 1998; accepted 21 February 1999