zithromax and Arteriosclerosis

Several lines of evidence have demonstrated an association between a variety of chronic bacterial infections and atherosclerotic cardiovascular disease. This has led to the proposal that antibiotic therapy might be helpful in the secondary prevention of atherosclerosis. A variety of smaller pilot studies have been reported testing this hypothesis and several large multicenter trials are also underway. The purpose of this review is to summarize the results of these studies and comment on their implications for the treatment of atherosclerosis.. Most of the antibiotic studies to date have been secondary prevention studies that have targeted patients exposed to Chlamydia pneumoniae. Most have used either azithromycin or roxithromycin with treatment courses ranging from a few days to 3 months. Several small studies of coronary artery disease patients have shown significant promise for reducing cardiovascular events such as death, myocardial infarction, or admission for unstable angina. However, other studies have not been so positive. Weekly Intervention with Zithromax for Atherosclerosis and its Related Disorders, WIZARD, the largest study to date, in which stable post-myocardial infarction patients were randomized to receive a 3-month course of azithromycin or placebo, demonstrated a significant reduction in death and myocardial infarction by 6 months, but this benefit was not sustained throughout the remaining course of follow-up. The Azithromycin and Coronary Events (ACES) and Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trials are ongoing and are testing the effect of more prolonged treatment duration.. A variety of antibiotic trials for the secondary prevention of atherosclerosis have been performed. Several pilot studies have shown significant positive clinical effects, but, thus far, no large randomized trial has confirmed those findings. Some concerns over the antibiotics chosen and the duration of treatment have been raised. Other trials are underway to address some of those concerns. In the meantime, no recommendation for the use of antibiotic therapy for the secondary prevention of atherosclerosis can yet be made.

Topics: Animals; Anti-Bacterial Agents; Arteriosclerosis; Azithromycin; C-Reactive Protein; Cardiovascular Diseases; Chlamydophila Infections; Chlamydophila pneumoniae; Clarithromycin; Coronary Artery Disease; Coronary Restenosis; Diet, Atherogenic; Fluoroquinolones; Gatifloxacin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Models, Animal; Myocardial Ischemia; Rabbits; Randomized Controlled Trials as Topic; Roxithromycin; Treatment Outcome

Azithromycin is the sole member of the macrolide sub-class, the azalides. Due to its altered chemical structure, azithromycin is characterized by a broader spectrum of activity, lower incidence of adverse events and drug interactions and a pharmacokinetic profile, that is in contrast to existing macrolides. Because of its high and prolonged cellular and tissue concentrations, patients are able to complete a course of azithromycin within a shorter timeframe as compared to other antibiotics. Azithromycin is widely used in the treatment of adult and pediatric respiratory tract infections. Continued research into azithromycin's utility has resulted in indication development for several devastating infections such as trachoma. Large-scale studies of its activity against Chlamydia pneumoniae related atherosclerosis are underway.

Topics: Adult; Anti-Bacterial Agents; Arteriosclerosis; Azithromycin; Bacteria; Child; Chlamydia Infections; Chlamydophila pneumoniae; Drug Resistance, Microbial; Humans; Respiratory Tract Infections; Trachoma

Topics: Animals; Anti-Bacterial Agents; Aorta; Arteriosclerosis; Azithromycin; Chlamydia Infections; Chlamydophila pneumoniae; Cholesterol, Dietary; Disease Models, Animal; Rabbits

Clinical trials to assess the merit of antibiotic intervention in the treatment of ischemic cardiovascular disease are now underway, spurred on by an association between Chlamydia pneumoniae and atherogenesis noted in epidemiologic investigations, histopathologic studies, and results from various animal models. The design of such clinical trials must take into account a number of issues: the primary event as strictly defined by objective criteria, the event rate in the chosen population, the potential treatment effect, the availability of patients, the underlying cause of their atherosclerotic disease, the determination of the C pneumoniae-infected population to study, the dose and duration of the antibiotic, and the length of follow-up. In the design of the WIZARD study (Weekly Intervention with Zithromax for Atherosclerosis and its Related Disorders), an attempt was made to take these issues under consideration. Patients were randomly assigned either to 600 mg/d zithromax for 3 days then 600 mg/wk for 11 additional weeks or to placebo. Patients in the study had a myocardial infarction at least 6 weeks previously, had no recent coronary artery bypass graft or percutaneous transluminal coronary angioplasty, and did not required long-term administration of antibiotics. Patients were required to have an immunoglobulin G titer to C pneumoniae of >/=1:16. The primary end point was the time to a composite of all-cause death, myocardial infarction, a revascularization procedure, or hospitalization for angina. The study enrolled 3500 patients, sufficient to detect a 25% reduction in the presumed 8% placebo event rate with 90% power. Follow-up will continue through the prespecified number of end points.

Topics: Anti-Bacterial Agents; Arteriosclerosis; Azithromycin; Chlamydia Infections; Clinical Trials as Topic; Humans; Research Design; Sensitivity and Specificity

Topics: Anti-Bacterial Agents; Arteriosclerosis; Azithromycin; Chlamydia Infections; Chlamydophila pneumoniae; Clinical Trials as Topic; Combined Modality Therapy; Humans; Research Design; Vaccines

Chlamydia pneumoniae is the third species of the genus Chlamydia and has been known to cause respiratory tract infections. Since the association between the seropositivity of C. pneumoniae and ischemic heart diseases was reported in 1988, the association between C. pneumoniae and atherosclerosis has been noteworthy. Positive findings of the association between C. pneumoniae and atherosclerosis have been reported as the result of seroepidemiological surveys, histological studies to detect C. pneumoniae in human atherosclerotic tissues, and animal infection models. These data supported that C. pneumoniae infection occurs in human vascular walls and may accelerate the foam cell formation of macrophage and smooth muscle cells, and may play a causative role in atherosclerosis. Several large-scale studies of the antimicrobial prevention of secondary cardiac events are in progress. The genome projects for C. pneumoniae have recently been reported. A number of issues remain unclear, however, and further intensive research is necessary.

Topics: Adult; Aged; Animals; Anti-Bacterial Agents; Arteriosclerosis; Azithromycin; Chlamydia Infections; Chlamydophila pneumoniae; Cholesterol; Clinical Trials as Topic; Endothelium, Vascular; Foam Cells; Genome, Bacterial; Humans; Macrophages; Mice; Mice, Transgenic; Middle Aged; Muscle, Smooth, Vascular; Myocardial Ischemia; Pneumonia, Bacterial; Rabbits; Seroepidemiologic Studies

Sero-epidemiological and experimental studies suggest that Chlamydia pneumoniae infections play an important role in the development of atherosclerosis. Clinical trials have shown contradictory results regarding the efficacy of antibiotics to prevent atherosclerosis-related complications in patients with coronary artery disease. Our aim was to study the effect of a short course of azithromycin on the incidence of cardiovascular events and peripheral vascular function in patients with stable peripheral arterial disease (PAD).. Five hundred and nine PAD-patients were randomised to receive either a 3-day course of azithromycin (500 mg daily) or placebo, with 2 years of follow-up. C. pneumoniae serology was determined at baseline. Clinical endpoints were death, coronary events (myocardial infarction, unstable angina, and/or coronary revascularization procedures), cerebral events (stroke, TIA, and/or carotid endarterectomy) and peripheral arterial complications (increased PAD-symptoms with decreased ankle-brachial index (ABPI, 0.1-point decrease after 12 months), and/or peripheral revascularization procedures).. Five hundred and nine patients (160 women) with an atherosclerotic risk factor profile were randomised, 257 patients to azithromycin and 252 to placebo. Four hundred and forty nine patients (88%) had intermittent claudication and 60 (12%) had critical limb ischemia. By 24-month follow up, 182 patients (36%) developed 252 complications (45 deaths, 34 coronary events, 34 cerebral events and 139 peripheral arterial complications). C. pneumoniae IgA-titres were associated with the development of cardiovascular events. Nevertheless, the number of complications (131 in the azithromycin group vs. 121 in the placebo group) and the number of patients that developed complications (98 (38%) in the azithromycin vs. 84 (33%) in the placebo group) was comparable in both treatment groups. Life table analysis showed no effect of azithromycin on survival or ABPI.. A short-term course of azithromycin offers no benefits for survival or ankle pressure in PAD-patients.

Topics: Aged; Anti-Bacterial Agents; Arteriosclerosis; Azithromycin; Chi-Square Distribution; Chlamydophila Infections; Chlamydophila pneumoniae; Double-Blind Method; Female; Humans; Male; Middle Aged; Peripheral Vascular Diseases; Statistics, Nonparametric; Treatment Outcome

Clinical trials to assess the merit of antibiotic intervention in the treatment of ischemic cardiovascular disease are now underway, spurred on by an association between Chlamydia pneumoniae and atherogenesis noted in epidemiologic investigations, histopathologic studies, and results from various animal models. The design of such clinical trials must take into account a number of issues: the primary event as strictly defined by objective criteria, the event rate in the chosen population, the potential treatment effect, the availability of patients, the underlying cause of their atherosclerotic disease, the determination of the C pneumoniae-infected population to study, the dose and duration of the antibiotic, and the length of follow-up. In the design of the WIZARD study (Weekly Intervention with Zithromax for Atherosclerosis and its Related Disorders), an attempt was made to take these issues under consideration. Patients were randomly assigned either to 600 mg/d zithromax for 3 days then 600 mg/wk for 11 additional weeks or to placebo. Patients in the study had a myocardial infarction at least 6 weeks previously, had no recent coronary artery bypass graft or percutaneous transluminal coronary angioplasty, and did not required long-term administration of antibiotics. Patients were required to have an immunoglobulin G titer to C pneumoniae of >/=1:16. The primary end point was the time to a composite of all-cause death, myocardial infarction, a revascularization procedure, or hospitalization for angina. The study enrolled 3500 patients, sufficient to detect a 25% reduction in the presumed 8% placebo event rate with 90% power. Follow-up will continue through the prespecified number of end points.

Topics: Anti-Bacterial Agents; Arteriosclerosis; Azithromycin; Chlamydia Infections; Clinical Trials as Topic; Humans; Research Design; Sensitivity and Specificity

To evaluate whether antimicrobial chemotherapy prevents acceleration of atherosclerotic lesion development induced by infection with Chlamydia pneumoniae.. ApoE-deficient mice which develop hyperlipidaemia and atherosclerosis spontaneously were inoculated intranasally with C. pneumoniae. Animals were treated with azithromycin for 6 weeks after the third inoculation and the atherosclerotic lesion areas in the aortic sinus were measured by computer-assisted morphometry.. At 12 weeks post-infection, infected untreated animals developed significantly larger lesion areas compared with sham-inoculated controls (8.7 x 10(4)+/-2.3 x 10(4) microm(2) versus 5.6 x 10(4)+/-2.4 x 10(4) microm(2)). However, there were no differences in lesion size of infected mice treated with azithromycin in comparison with untreated infected controls (11.0 x 10(4)+/-3.0 x 10(4) microm(2) versus 8.7 x 10(4)+/-2.3 x 10(4) microm(2)).. Antibiotic treatment against C. pneumoniae has no beneficial effects on hyperlipidaemia-induced atherosclerosis accelerated by C. pneumoniae in a mouse model.

Topics: Animals; Anti-Bacterial Agents; Apolipoproteins E; Arteriosclerosis; Azithromycin; Chlamydophila Infections; Chlamydophila pneumoniae; Chronic Disease; Male; Mice

Topics: Animals; Anti-Bacterial Agents; Arteriosclerosis; Azithromycin; Chlamydophila Infections; Chlamydophila pneumoniae; Coronary Disease; Drug Resistance, Bacterial; Drug Therapy, Combination; Fluoroquinolones; Gatifloxacin; Humans

Topics: Adolescent; Animals; Anti-Bacterial Agents; Arteriosclerosis; Azithromycin; Chlamydophila Infections; Chlamydophila pneumoniae; Clinical Trials as Topic; Female; Foam Cells; Humans; Hypercholesterolemia; Lipids; Muscle, Smooth, Vascular; Risk Factors

Topics: Anti-Bacterial Agents; Antibodies, Bacterial; Arteriosclerosis; Azithromycin; Chlamydophila Infections; Chlamydophila pneumoniae; Follow-Up Studies; Humans; Morbidity; Myocardial Infarction; Randomized Controlled Trials as Topic; Recurrence; Roxithromycin; Sample Size; Treatment Outcome

Chlamydia pneumoniae infection can exacerbate atherosclerosis in animals. To test the hypothesis that antibiotic therapy inhibits the atherogenic effects of C. pneumoniae infection, 10-week-old apolipoprotein E (ApoE) null mice were infected with C. pneumoniae or placebo, were treated for 2 weeks after infection with azithromycin or placebo, and were killed at 20 weeks of age. Infection did not affect the size of the aortic lesion, and antibiotic treatment had no effect. Another group of mice, 12-week-old ApoE mice, were infected with C. pneumoniae or placebo, were treated for 2 weeks after infection with azithromycin or placebo, and were killed at 26 weeks of age. C. pneumoniae infection increased the size of the lesion in infected mice, but azithromycin did not reduce the size of the aortic lesion in infected mice. Therefore, immediate therapy of acute infection may be necessary to prevent the proatherogenic effects of C. pneumoniae infection.

Topics: Animals; Anti-Bacterial Agents; Antibodies, Bacterial; Aorta; Apolipoproteins E; Arteriosclerosis; Azithromycin; Chlamydophila Infections; Chlamydophila pneumoniae; Female; Lipids; Mice; Mice, Inbred C57BL; Polymerase Chain Reaction

Observational data strongly suggest an association between Chlamydia pneumoniae and atherosclerotic cardiovascular disease. However, few studies have mechanistically linked C. pneumoniae to vascular remodeling. The purpose of the present study was to examine the mechanistic relationship between C. pneumoniae and human vascular smooth muscle cell (VSMC) physiology. We sought to determine the influence of human VSMC infection by C. pneumoniae on (1) VSMC proliferation and (2) activation of the proinflammatory and proliferative transcription factors nuclear factor kappaB (NF-kappaB) and activator protein 1 (AP-1).. C. pneumoniae was grown and isolated from Hep 2 cells. Human aortic VSMCs were inoculated with C. pneumoniae in the presence and absence of the azalide antibiotic azithromycin. Cell proliferation was assayed by direct cell counting 48 h following infection. Two hours following infection, nuclear extracts were isolated, and activation of both NF-kappaB and AP-1 was assessed by electrophoretic mobility shift assay.. Compared with control, C. pneumoniae infection stimulated VSMC proliferation (P < 0.05) and induced both NF-kappaB and AP-1 DNA binding activity. These effects were eliminated by concurrent treatment with azithromycin.. VSMC infection with C. pneumoniae activates proliferative intracellular signals and stimulates cell growth. These data implicate C. pneumoniae as a pathogenic mediator and a potential therapeutic target in the prevention of atherosclerotic disease.

Topics: Arteriosclerosis; Azithromycin; Cell Division; Cells, Cultured; Chlamydophila pneumoniae; DNA; Humans; Immunohistochemistry; Muscle, Smooth, Vascular; NF-kappa B; Transcription Factor AP-1

Chlamydia pneumoniae infection has been associated with atherosclerosis by serological studies and detection of bacterial antigen within plaque. We sought to evaluate a possible causal role in an animal model.. Thirty New Zealand White rabbits were given three separate intranasal inoculations of either C pneumoniae (n = 20) or saline (n = 10) at 3-week intervals and fed chow enriched with a small amount (0.25%) of cholesterol. Immediately after the final inoculation, infected and control rabbits were randomized and begun on a 7-week course of azithromycin or no therapy. Three months after the final inoculation, rabbits were euthanatized and sections of thoracic aortas were blindly evaluated microscopically for maximal intimal thickness (MIT), percentage of luminal circumference involved (PLCI), and plaque area index (PAI) of atherosclerosis. Vascular chlamydial antigen was assessed by direct immunofluorescence. MIT differed among treatment groups (P=.009), showing an increase in infected rabbits (0.55 mm; SE = 0.15 mm) compared with uninfected controls (0.16 mm; SE = 0.06 mm) and with infected rabbits receiving antibiotics (0.20 mm; SE = 0.03 mm) (both P<.025), whereas MIT in infected/treated versus control rabbits did not differ. PLCI also tended to differ (P<.1) and PAI differed significantly (P<.01) among groups with a similar pattern. Chlamydial antigen was detected in 2 untreated, 3 treated, and 0 control animals.. Intranasal C pneumoniae infection accelerates intimal thickening in rabbits given a modestly cholesterol-enhanced diet. In addition, weekly treatment with azithromycin after infectious exposure prevents accelerated intimal thickening. These findings strengthen the etiologic link between C pneumoniae and atherosclerosis and should stimulate additional animal and human studies, including clinical antibiotic trials.

Topics: Animals; Anti-Bacterial Agents; Antigens, Bacterial; Aorta; Arteriosclerosis; Azithromycin; Chlamydia Infections; Chlamydophila pneumoniae; Female; Fluorescent Antibody Technique, Indirect; Humans; Rabbits; Specific Pathogen-Free Organisms

Topics: Animals; Anti-Bacterial Agents; Arteriosclerosis; Azithromycin; Chlamydia Infections; Chlamydophila pneumoniae; Humans; Rabbits