Effect of Macrolides on Peripheral Arterial Disease Depends on Patient Selection and Adequate Treatment

Abstract

Vainas et al. investigated a possible effect of a 3-day azithromycin course on peripheral arterial disease (PAD) during 2 years. Peripheral arterial complications were observed in 23% of azithromycin-treated and 20% of placebo-treated patients. Vainas et al. concluded that a short-term course of azithromycin does not influence PAD.1Vainas T. Stassen F.R.M. Schurink G.W.H. Tordoir J.H.M. Welten R.J.Th.H. van den Akker L.H.J.M. et al.Secondary prevention of atherosclerosis through Chlamydia pneumoniae eradication (SPACE Trial): a randomised clinical trial in patients with peripheral arterial disease.Eur J Vasc Endovasc Surg. 2005; 29: 403-411Google Scholar In contrast, our group showed that administration of roxithromycin for 28 days prevents progression of PAD in Chlamydia pneumoniae seropositive men. Limitation of walking distance to 200 m or less was observed in 20% of roxithromycin-treated and 65% of placebo-treated patients. Five invasive revascularizations were carried out in 20% of roxithromycin-treated patients compared to 29 interventions in 45% of placebo-treated patients during 2.7 years.2Wiesli P. Czerwenka W. Meniconi A. Maly F.E. Hoffmann U. Vetter W. et al.Roxithromycin treatment prevents progression of peripheral arterial occlusive disease in Chlamydia pneumoniae seropositive men.Circulation. 2002; 105: 2646-2652Google Scholar The striking difference between the two studies regarding the effect of macrolides on PAD needs explanation. Patients were selected differently for the two studies. Vainas et al. selected patients who either had an IgA titer>16 (mean 28) EIUs or were C. pneumoniae seronegative. In contrast, an IgG titer≥1/128 was inclusion criterion of our study, median C. pneumoniae antibody titers were 1/256 (IgG) and 1/64 (IgA). The percentage of patients undergoing severe impairment of PAD clearly differed between the placebo group of Vainas' study (20%) and our study (65%). Duration of antibiotic treatment was different in the two studies. Azithromycin administered for 3 days—though characterized by a serum and tissue half life time of several days—is expected to have a less accentuated anti-chlamydial effect than roxithromycin given for 28 days in our study. A possible effect of macrolides on PAD depends on (I) selection of patients with clinically relevant endovascular infection with C. pneumoniae and (II) treatment of these patients with an effective regimen. The relevance of patient selection is often underestimated. We selected—in contrast to Vainas et al.—patients with high antibody titers (IgG≥1/128) and a high clinical activity of peripheral atherosclerosis (severe impairment of PAD was observed in 65% of the placebo-treated patients). These features might indicate endovascular chlamydial disease. In our study, a significant association between C. pneumoniae seropositivity and incidence of PAD confirmed the involvement of C. pneumoniae.3Krayenbuehl P. Wiesli P. Maly F.E. Vetter W. Schulthess G. Progression of peripheral arterial occlusive disease is associated with Chlamydia pneumoniae seropositivity and can be inhibited by antibiotic treatment.Atherosclerosis. 2005; 179: 103-110Google Scholar It is worth noting, that C. pneumoniae seropositivity was also significantly related to peripheral arterial events in the study by Vainas et al.1Vainas T. Stassen F.R.M. Schurink G.W.H. Tordoir J.H.M. Welten R.J.Th.H. van den Akker L.H.J.M. et al.Secondary prevention of atherosclerosis through Chlamydia pneumoniae eradication (SPACE Trial): a randomised clinical trial in patients with peripheral arterial disease.Eur J Vasc Endovasc Surg. 2005; 29: 403-411Google Scholar It will be subject of further studies to evaluate whether a high clinical activity of peripheral atherosclerosis in presence of high C. pneumoniae antibody titers is a reliable criterion for patient selection and whether administration of macrolides during 1 month is an optimum regimen. A further indicator of endovascular infection with C. pneumoniae might be elevated concentrations of serum homocysteine.4Wiesli P. Maly F.E. Meniconi A. Czerwenka W. Hoffmann U. Vetter W. et al.Chlamydia pneumoniae seropositivity and hyperhomocysteinemia are linked in patients with atherosclerosis.Clin Chem. 2001; 47: 1304-1306Google Scholar In both Vainas' and our study, C. pneumoniae antibodies were preferentially associated with atherosclerosis of peripheral arteries. Preference of C. pneumoniae for peripheral arteries is conceivable since peripheral arteries have a different embryological origin and a different histological constitution than coronary and cerebral arteries.5Shimizu M. Pelisek J. Niko S. Vasculogenesis and angiogenesis depende on the developmental origin in the arterial tree.Curr Med Chem. 2002; 9: 1619-1630Google Scholar