Antibiotics for Prevention of Myocardial Infarction? Not Yet!

Atherosclerotic cardiovascular disease is the leading cause of death in the United States and, by 2020, is projected to be the leading cause of disability in the world.¹ Many important and preventable risk factors for atherosclerotic disease have been identified, including hypercholesterolemia, hypertension, cigarette smoking, diabetes, obesity, and physical inactivity. Nevertheless, additional environmental factors probably contribute to the initiation, propagation, and rupture of atherosclerotic plaques, and, ultimately, to clinical atherothrombotic events. The possibility that infection may be one of these factors was hypothesized more than 100 years ago² —a hypothesis that has attracted renewed scientific interest recently.

Epidemiological, basic, and clinical investigations during the past decade have suggested, but not yet proven, that infectious agents may in fact contribute to atherosclerotic vascular disease. The organisms implicated most often include the herpesviruses, particularly cytomegalovirus, Chlamydia pneumoniae, and, less convincingly, Helicobacter pylori.^{3 - 4} Periodontitis also has been linked to increased risk of atherosclerotic vascular disease.⁵ Hypothesized mechanisms by which infection could cause vascular disease include direct infection of the arterial wall, systemic infection leading to endotoxin injury of the endothelium, autoimmunity (eg, through cross-reactivity of heat-shock proteins with bacterial antigens), systemic inflammation, or increases in inflammatory mediators, such as C-reactive protein, fibrinogen, and white blood cell count.^{3 - 4}

A leading bacterial culprit for promoting atherosclerosis is C pneumoniae, a gram-negative bacterium that principally causes upper respiratory tract infections. Positive C pneumoniae antibody titers, present in approximately half of adults, have been associated consistently with increased risk of atherosclerotic disease.³ Chlamydia pneumoniae has been identified and cultured from atheroma and can infect vascular cells in vitro.^{4 ,6} The organism also can induce atherosclerosis in animal models.^{4 ,6} However, C pneumoniae and other infectious agents may be only "innocent bystanders" in human atherosclerotic plaques, not true causative agents.⁴

Additional research needed to support an infectious origin for atherosclerotic disease includes clinical trials to show that antibiotics might prevent cardiovascular events. If such trials showed efficacy, antibiotics could provide a means for preventing or treating atherosclerosis. In the past year, the macrolide antibiotic azithromycin was shown to prevent accelerated intimal thickening in cholesterol-fed rabbits that had repeated nasal inoculations of C pneumoniae.⁷ Two small secondary prevention trials using macrolide treatment in humans also have been promising. A prospective study showed that following myocardial infarction (MI), men with elevated C pneumoniae antibody titers who were not treated with azithromycin had a greatly increased risk of recurrent cardiovascular disease events compared with both titer-positive MI patients treated 3 to 6 days with azithromycin and untreated patients with negative titers for C pneumoniae.⁸ Likewise, a randomized, double-blind, placebo-controlled pilot study (n=202) showed that 30 days of treatment with roxithromycin significantly reduced recurrent coronary events in patients with unstable angina or non–Q-wave MI.⁹ Additional secondary prevention trials are under way.⁶

In this issue of JAMA, Meier and colleagues¹⁰ provide new evidence from a case-control study to suggest that antibiotics may prevent a first MI. These investigators used a general practice database in the United Kingdom to compare antibiotic use during a 3-year period before first MI in case patients vs a comparable period in control patients. The study was large and, to enhance the validity of the results, the investigators matched or statistically adjusted for a number of potentially confounding variables. The main finding was that MI cases, compared with controls, were less likely to have used tetracycline or quinolone antibiotics in the past. This association is consistent with the hypothesis that these antibiotics might prevent a first MI. In contrast, there was no association between MI occurrence and past use of several other classes of antibiotics, including macrolides, sulfonamides, penicillins, or cephalosporins. The finding of no protective association for macrolides at first seems surprising, but as Meier et al¹⁰ point out, the principal macrolide in use was erythromycin, which is not very effective against C pneumoniae.

Meier et al¹⁰ appropriately concluded that their study provides only indirect evidence for an infectious origin for MI. A few additional points need emphasis. First, their study was not an experimental trial, so confounding and selection biases might explain the results. Second, the study excluded patients with the major cardiovascular risk factors, such as hypertension, diabetes and dyslipidemia, thereby making the study sample not representative of the general population at risk for MI. Third and most important, although less past treatment with tetracycline and quinolone among MI cases than controls is consistent with the hypothesis that antibiotics could prevent MI, paradoxically, it is also consistent with MI cases having had fewer infections needing antibiotic treatment than controls. Unfortunately, it was impossible for Meier et al to measure antibody titers to establish infection rates. Fourth, if antibiotics could prevent MI over a period as short as 3 years, the antibiotic effect may pertain more to the prevention of plaque rupture or thrombosis than preventing atherosclerosis per se. For example, antibiotics may prevent atherosclerotic events through a nonspecific anti-inflammatory effect rather than by an antibacterial effect.^{4 ,11 - 12}

What is the message of the study by Meier et al¹⁰ for the practicing physician? The findings should be considered part of research in progress on the possible infectious origin of atherosclerotic vascular disease. Antibiotics are not indicated currently for the prevention or treatment of MI. Moreover, there is a great deal of uncertainty in this research area about exactly what types of infection should be eliminated, which patients might be appropriate for intervention with antimicrobials, and when and how long antibiotic intervention should occur. Large, randomized clinical trials are needed to test the hypothesis that antibiotics may be beneficial beyond established interventions for primary or secondary prevention of MI. Even if antibiotic trials suggest a possible bacterial contribution to atherosclerotic disease, widespread antibiotic prophylaxis would need to be undertaken cautiously because of the likelihood of promoting drug-resistant bacteria. In the meantime, physicians should emphasize interventions proven to prevent first MI—lipid lowering, hypertension control, and smoking cessation.