Parallel with the mounting evidence that atherosclerosis has a major inflammatory component, provoking agents that may initiate and drive this process have been sought. Infectious agents such as Chlamydia pneumoniae have been alleged to be activators of inflammation that may contribute to atherosclerosis and thus coronary artery disease (CAD) and its associated complications. A logical extension of this theory is whether treating C pneumoniae infection with antibiotics and/or modulating inflammatory processes can affect CAD and its sequelae. This article discusses the potential role of C pneumoniae in atherosclerosis, its detection, and the rationale for antibiotics. Additionally, it summarizes the current randomized clinical trials of antichlamydial antibiotics in patients with CAD and draws conclusions based on the results.
Coronary artery disease (CAD) is a major cause of morbidity and mortality in humans worldwide. By the year 2020, CAD is predicted to be the leading cause of death and disability in the world.
1
Recently, further understanding at the molecular level revealed that atherosclerosis is an inflammatory disease; thus, an infection being linked to CAD is biologically plausible.
2
A focus on the triggers of the earliest changes of atherosclerosis (endothelial dysfunction) and inflammation that precede atherosclerotic lesions has centered on several microorganisms.The infectious hypothesis of atherosclerosis was postulated during the latter part of the 19th century: Gilbert and Leon described fatty sclerotic change in an arterial wall of a rabbit after slight mechanical injury coupled with injection of pathogenic bacteria.
3
Chlamydia pneumoniae, a gramnegative bacterium that causes upper respiratory tract infection, is associated with CAD. The association of C pneumoniae with CAD was first noted in 1988 by Saikku et al4
in Finland. Since then, a large body of research has shown that C pneumoniae is associated seroepidemiologically with CAD, although not all studies or cohorts have found a significant relationship after correcting for con-founders. Additionally, direct pathological evidence revealing the presence of C pneumoniae in atherosclerotic plaques and the ability to culture viable C pneumoniae from plaque have added credence to this hypothesis. However, the issue of the “innocent bystander” has not been clarified. Moreover, animal models (rabbits, chickens, and mice) confirm C pneumoniae-induced atherogenesis.5
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Although C pneumoniae is considered the pathogen most likely to have an etiologic role in CAD, this causality in humans is not fully evident. Nonetheless, large randomized controlled trials are analyzing the effect of treating patients with CAD and its associated complications with antibiotics that have activity against C pneumoniae.METHODS
The English-language scientific literature was reviewed primarily by searching MEDLINE and EMBASE databases for the period 1976 through July 2002. Keywords used in the search included chlamydia, pneumoniae, coronary, artery, disease, atherosclerosis, antibiotics, and inflammation. The reference lists of articles found through these searches were also reviewed for relevant articles. In addition, links on Web sites containing published articles were searched for relevant information.
ATHEROSCLEROSIS, INFLAMMATION, AND INFECTION
The body's inflammatory response plays an important role in the progression of atherosclerosis and vulnerable plaque.
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One theory is that, in certain genetically susceptible people, infection with common organisms such as C pneumoniae may lead to a localized infection and a chronic inflammatory reaction that may accelerate atherosclerosis.10
Specifically, how can C pneumoniae affect the biology of atherosclerotic plaque? Four theories are described subsequently.- 1.Infection with C pneumoniae may contribute to endothelial dysfunction, which is believed to underlie and precede the pathological atherosclerotic process.11Inoculation of apolipoprotein E knockout mice (which develop atherosclerotic lesions spontaneously) with C pneumoniae results in endothelial dysfunction via the nitric oxide pathway.12Also, infected endothelial cells produce increased amounts of tissue factor, which is associated with thrombosis.13
- 2.C pneumoniae has been shown to infect components of atherosclerotic plaque, including endothelial cells, foam cells, and smooth muscle cells.14,15,16In addition, C pneumoniae has been found in monocytes and macrophages; systemic circulation and transendothelial migration make them a potential vector system for chlamydial distribution.17Macrophages infected with C pneumoniae are capable of transmitting infection to human coronary artery endothelial cells with direct cellular contact. Human coronary artery endothelial cells infected with C pneumoniae produce more interleukin 8 than do control cells.18Many studies have confirmed that infection with C pneumoniae is positively associated with inflammatory markers, including C-reactive protein, procoagulants (fibrinogen, plasminogen activator inhibitor 1, prostacyclin, factor VII), cytokines (interleukin 6, interleukin 8, tumor necrosis factor a), chemokines (monocyte chemotactic protein 1), nuclear factor-K B, and cellular adhesion molecules (intercellular and vascular cell adhesion molecule 1).16,18,19,20,21,22,23,24,25In addition to plaque growth and the promotion of atherothrombosis, these factors contribute to weakening and plaque rupture at the shoulder region.26,27,28,29
- 3.Components of C pneumoniae (ie, nonviable organisms) appear to have inflammatory effects. Several studies have reported that cardiovascular risk from prior chlamydial infection can be linked to certain antigens. Certain C pneumoniae antigens (40, 42, 52, 54, 60, 70, and 98 kd) appear to be more involved than others in the general immune response after infection, and chronic antibody responses to these may be associated with atherosclerosis.30,31,32C pneumoniae endotoxin (lipopolysaccharide) has also been shown to induce inflammatory cytokines, increase low-density lipoprotein cholesterol uptake, and transform mononuclear phagocytes into foam cells.28,33Other C pneumoniae products, including its heat shock protein 60, promote inflammation, can modulate oxidation of lipoproteins, and activate macrophage atherogenic functions.2,27,29,34The latter inflammation may be due in part to antigenic mimicry or an immunological cross-reactivity between C pneumoniae heat shock protein 60 and selfantigens (because of a certain degree of genetic homology).35This mimicry has been noted between C pneumoniae and the a myosin heavy chain of heart muscle.36
- 4.Several animal trials lend credence to the involvement of C pneumoniae in atherosclerosis. Intranasal C pneumoniae infection accelerates intimal thickening in rabbits given a modest cholesterol-enhanced diet; furthermore, weekly treatment with azithromycin after infectious exposure prevents accelerated intimal thickening.7In a similar rabbit model of atherosclerosis (nasopharyngeal inoculation with C pneumoniae), early treatment with azithromycin prevented atherosclerotic plaques; delayed treatment was ineffective.5
Possible ways in which C pneumoniae may affect atherosclerotic lesions of CAD are listed in Table 1.
Table 1Specific Factors That May Link Chlamydia pneumoniae Infection and Coronary Artery Disease
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DETECTION OF C pneumoniae
The meaning of anti-C pneumoniae IgG titers and the importance of their change is still debated. It is uncertain whether antibodies to C pneumoniae reflect active infection, past infection, chronic infection, or antigenic cross-reactivity. Also, it is unknown whether an anti-C pneumoniae IgG titer of 1:64 confers more or less of a risk than a titer of 1:16.
Infection with C pneumoniae is ubiquitous in all populations with CAD that have been studied. Seropositivity is high and appears to increase with age and male sex, ranging from 20% to 84% in various population studies.
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Of the published epidemiological evidence, most studies have found a 1.5- to 2-fold larger odds ratio for CAD in individuals exposed to C pneumoniae.50
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However, some studies have found no association between C pneumoniae and CAD and/or its manifestations.56
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Results from various serologic studies are divergent because of differing populations and differing antibody serologic markers (eg, serum IgG, IgA, or IgM), sometimes in combination and at various “cutoff” levels. Odds ratios were adjusted for confounders to different extents, confounding was addressed to different depths, and study methods lent themselves to bias in differing areas. Also, subgroup analyses tended to be based on small numbers and therefore prone to statistical bias. The measuring instrument, primarily immunofluorescence and enzyme immunoassay, is operator dependent.
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Also, titers of C pneumoniae antibody are not always positively associated with C pneumoniae organism in atheroma; they may reflect a cross-reactivity to non-C pneumoniae antigens.59
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Several DNA sequencing studies revealed no differences between coronary isolates and respiratory reference strains, suggesting that common respiratory strains gain access to the systemic circulation.
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However, serologic results (antichlamydial IgG, IgA, and IgM) do not always correlate with direct detection results or with individual endovascular infection.63
Also, persons without measurable antibodies can show cell-mediated immunity to C pneumoniae, indicating that they have been exposed to the bacteria.64
In one study, some patients with C pneumoniae in their atherosclerotic plaques had no C pneumoniae antibodies.31
A study of human atherectomy samples found no relationship between the frequency of C pneumoniae detection and C pneumoniae-specific antibody titers.65
This raises the question, “What are we actually measuring with C pneumoniae serology?”Pathological studies vary in population, atheroma samples, and sensitivities and specificities of tests used (immunocytochemistry, polymerase chain reaction [PCR], enzyme immunoassay, electron microscopy, culture, immunofluorescence), and they do not rule out the possibility that C pneumoniae may be an innocent bystander in the process. In addition, uncertainties of results with PCR analysis and C pneumoniae occur and may reflect operator dependency; moreover, the detection rate (ranging from 0%-73%) may vary markedly with the number and type of primers used.
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Using more than 1 test may also improve detection rates.68
Overall, study results support the finding of a high prevalence of C pneumoniae in atherosclerotic lesions. A logical extension of these pathological findings is whether these organisms detected inside coronary atherosclerotic lesions are alive or dead.In a study involving culturing of fresh atherosclerotic coronary artery specimens, a substantial proportion (16%) harbored viable C pneumoniae.
63
In a study of 12 cases, C pneumoniae was detected in 7; C pneumoniae was cultured from atherosclerotic plaques in only 1 patient with severe CAD.69
The organism was found in the atheromas of this patient by PCR assay, immunocytochemistry, electron microscopy, and in situ hybridization. In a study performed in Asia, C pneumoniae was detected by PCR and/or immuno-histochemical staining in 69% of 29 atherectomy specimens from patients with CAD; however, the investigators were unable to culture viable organisms from a single case.68
These studies suggest that, although it is possible to culture live viable C pneumoniae organisms from coronary plaques, in most cases, culture comes back negative. This may reflect the difficulty in culturing C pneumoniae or the nonviability of the organism in storage (compared to fresh specimens). In contrast, this may suggest that after initial infection with C pneumoniae the body may destroy the organism, but the dead organism may then become a nidus for chronic inflammation.
In summary, it remains unclear whether C pneumoniae actually initiates atherosclerotic injury, facilitates its progression, or merely colonizes preexisting atheromas.
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RATIONALE FOR ANTIBIOTICS AND THEIR MECHANISMS
Four classes of antibiotics have activity against C pneumoniae: quinolones, macrolides, tetracyclines, and anti-tuberculars (rifapentine, rifampin).
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Some classes appear to have anti-inflammatory activity. All the antibiotic trials reported thus far used macrolides, the focus of this section.Macrolide antibiotics have several anti-inflammatory effects. They affect migration of inflammatory cells and production of proinflammatory mediators, cytokines, and superoxide by activated leukocytes.
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By subduing inflammation, these antibiotics may stabilize atheromatous plaque, which may in part explain some of the benefits noted in the trials involving patients with acute coronary syndromes.Erythromycin increases constitutive nitric oxide synthase and thus nitric oxide release in human endothelial cells.
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Both erythromycin and roxithromycin have antioxidant properties.73
In a rat carrageenin pleurisy model of acute inflammation, roxithromycin appeared to be superior to clarithromycin and erythromycin in reducing the inflammatory reaction (measured by macrophage production of interleukin 1, interleukin 6, and tumor necrosis factor a); azithromycin had only a slight effect.79
A study investigating the potential anti-inflammatory activity of 3 macrolide antibiotics (azithromycin, roxithromycin, and clarithromycin) used an in vitro model of transendothelial migration. Both azithromycin and roxithromycin caused significant decreases in neutrophil and monocyte transendothelial migration (partially due to inhibition of interleukin 8 and monocyte chemotactic protein 1 production); clarithromycin had no detectable effect in either group. Azithromycin caused significant decreases in interleukin 8 and monocyte chemotactic protein 1, whereas roxithromycin significantly decreased interleukin 8. This study indicates heterogeneity in the anti-inflammatory activity of these antibiotics from the same class.
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A study of human cultured macrophages measured macrophage activity (Kor channel conductance) and compared roxithromycin and tetracycline.80
Roxithromycin (not tetracycline) produced significant reductions in whole-cell conductance, suggesting suppression of macrophage activity, which may partly explain its benefit in acute coronary syndromes.One crucial issue is whether antibiotics are bactericidal in all tissues. In one study, neither azithromycin nor rifampin inhibited C pneumoniae growth within monocytes. Thus, circulating monocytes carrying C pneumoniae with reduced antimicrobial susceptibility could initiate reinfection or promote atherosclerosis by the release of proin-flammatory mediators.
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In contrast, actively replicating C pneumoniae in coronary endothelial cells and smooth muscle cells can be eliminated with quinolones (ofloxacin, levofloxacin, trovafloxacin, and moxifloxacin), macrolides (erythromycin, azithromycin, and roxithromycin), and antituberculars (rifapentine and rifampin; rifampin was the most effective drug overall).71
Antibiotic susceptibility profiles of C pneumoniae strains recovered from arteriosclerotic coronary arteries were described recently.
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In vitro susceptibilities to 5 cardiovascular C pneumoniae isolates did not differ significantly from respiratory strains in their patterns of susceptibility to azithromycin, erythromycin, roxithromycin, ofloxacin, doxycycline, rifampin, and penicillin G. Rox-ithromycin was the most active macrolide, and rifampin was the most effective drug overall.Sinisalo et al
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investigated the effect of 4 months of doxycycline therapy on serologic markers of C pneumoniae infection and coronary risk factors, and they found no effect on C pneumoniae antibodies or CAD risk factors. In a small randomized study of patients with carotid atherosclerosis scheduled for surgery, C pneumoniae was eradicated in 69% (11/16) who received roxithromycin treatment (150 mg twice daily for 26 days) vs 25% (4/16) who did not receive treatment (P=.03).84
This suggests that roxithromycin is effective in reducing the bacterial burden of C pneumoniae within atherosclerotic plaques, although treatment for long periods may be required for complete eradication. In a randomized, prospective, double-blind, placebo-controlled trial of 40 male patients with documented CAD and positive C pneumoniae-IgG antibody titers, treatment with azithromycin for 5 weeks had a favorable affect on endothelial function irrespective of antibody titer levels; placebo had no effect.72
Azithromycin therapy also resulted in a significant decrease of E-selectin and von Willebrand factor levels; however, C-reactive protein levels were not significantly altered by treatment with either azithromycin or placebo.In acute coronary syndromes, macrophages elaborate metalloproteinase enzymes (eg, collagenase, stromelysin, and gelatinase), which may digest structural components of the fibrous cap and predispose to plaque rupture. Tetracycline antibiotics have been shown to inhibit collagenase activity in vivo and in vitro. Macrolides may possess similar qualities.
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Certain antibiotics or combinations may have greater efficacy. “Triple therapeutic” regimens have been used for another chronic infection of the stomach, Helicobacter pylori, with efficacy, but more research is needed.In summary, the effects of antibiotics begin to occur within 5 weeks and appear to occur irrespective of C pneumoniae serology; antibiotics do not affect IgG levels, but they do affect various mediators of inflammation and atherosclerosis (Table 2).
Table 2Anti-inflammatory Effects of Macrolide Antibiotics
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RANDOMIZED CONTROLLED TRIALS
Three main populations with positive C pneumoniae serology that were randomized to antibiotics have been studied.
After Myocardial Infarction
Gupta et al
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at St George's Hospital in London performed a pilot trial that suggested a benefit with a brief course of azithromycin (3-6 days) in men who had had a myocardial infarction (MI) and had a high titer of anti-C pneumoniae IgG (Table 3). The WIZARD (Weekly Intervention with Zithromax for Atherosclerosis and its Related Disorders) trial was the logical extension of this pilot study. It used short-term treatment with azithromycin (3 months) and at a mean of 2.5 years’ follow-up found no significant effect on cardiovascular events (Table 3). There appeared to be an early benefit after treatment with azithromycin in the risk of MI, but it was not sustained.91
The maximal benefit, although not significant, was obtained in smokers (hazard ratio, 0.76; 95% confidence interval [CI], 0.581.00; P=.05) and in diabetic patients (hazard ratio, 0.80; 95% CI, 0.64-1.01; P=.06). The WIZARD trial had 2 phases: 3300 patients were enrolled in the original trial; subsequently, the trial reopened enrollment and recruited to a total of 7724 patients. It would be instructive to know whether patients in the original cohort who were followed up longer (3 years vs 1.5 years) had a significant event reduction compared with those enrolled later. The small ongoing CROAATS (Croatian Azithromycin in Atherosclerosis Study) is analyzing the effect on cardiovascular events of approximately 3 weeks of azithromycin therapy given on 3 days to post-MI patients with 2 positive anti-C pneumoniae IgG titers obtained 2 months apart (Table 3).Table 3Randomized Controlled Trials of Antibiotics in Post-MI Patients
| Trial | Study population | Treatment | End point | Results |
|---|---|---|---|---|
| St George's Hospital, 87 London | 220 consecutive male outpatients tested for IgG to Chlamydia pneumoniae; C pneumoniae negative, anti-C pneumoniae IgG 1:8-1:32 and anti-C pneumoniae IgG ≥1:64 | Randomized patients with IgG ≥1:64 to 3-6 days of azithromycin, 500 mg/d, or placebo; follow-up, 18 mo | Primary (composite): nonfatal MI, unstable angina, cardiovascular death Secondary: anti-C pneumoniae titers |
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| WIZARD 88 , 89 international multicenter trial | 7724 patients (83% male) ≥18 y with documented MI (>6 wk post-MI); IgG anti-C pneumoniae titer ≥1:16 | Azithromycin (Zithromax) for 3 mo (600 mg/d for 3 days, then 600 mg every week for 11 wk) vs placebo; mean follow-up, 2.5 y | Primary (composite): recurrent MI, all-cause mortality, revascularization, hospitalization for angina/ischemia Secondary: anti-C pneumoniae titers, levels of C-reactive protein, tumor necrosis factor a, and fibrinogen | No significant reduction in the primary composite end point (hazard ratio 0.93; P=.23) or in any of the end point components: baseline titer of IgG antibodies against C pneumoniae had no effect on outcome |
| CROAATS, 90 Zagreb, Croatia | 340 patients with documented MI and 2 seropositive serum samples (IgG anti-C pneumoniae titer ≥ 1:20) obtained 2 mo apart at 6 study sites | Azithromycin, 3 cycles of 500 mg once daily for 3 days, starting on days 1, 10, and 20 (total dose, 4500 mg) vs placebo; follow-up, 18 mo |
| Expected in 2004 |
* CI = confidence interval; CROAATS = Croatian Azithromycin in Atherosclerosis Study; MI = myocardial infarction; NS = not significant; OR = odds ratio; WIZARD = Weekly Intervention with Zithromax for Atherosclerosis and its Related Disorders.
† Small pilot study.
In summary, short-term antibiotic treatment in patients with a history of MI and positive C pneumoniae titers does not significantly reduce cardiovascular events.
Coronary Artery Disease
In the ACADEMIC (Azithromycin in Coronary Artery Disease: Elimination of Myocardial Infection with Chlamydia) study, azithromycin treatment for 3 months did not affect cardiovascular events, but at 6 months, it reduced inflammatory markers. The ACADEMIC study defined chronic CAD as previous MI, bypass surgery, or greater than 50% angiographic stenosis of one or more major coronary arteries. C pneumoniae antibody titers were unchanged (Table 4).
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ACES (Azithromycin and Coronary Events Study) is unique in that it will treat patients with azithromycin for 1 year; also, seropositivity to C pneumoniae is not an inclusion criterion (but the investigators expect about 80% of patients to be seropositive with an IgG titer ≥1:8). In addition, ACES will study C pneumoniae DNA (detected by PCR) located in peripheral blood mononuclear cells (Table 4). The ongoing MARBLE (Might Azithromycin Reduce Bypass List Events?) trial is treating patients who are awaiting bypass surgery with long-term antibiotic therapy in an attempt to decrease cardiovascular events (Table 4).Table 4Randomized Controlled Trials of Antibiotics for CAD
| Trial | Study population | Treatment | End point | Results |
|---|---|---|---|---|
| ACADEMIC 92 ,
Randomized secondary prevention trial of azithromycin in patients with coronary artery disease and serological evidence for Chlamydia pneumoniae infection: the Azithromycin in Coronary Artery Disease: Elimination of Myocardial Infection with Chlamydia (ACADEMIC) study. Circulation. 1999; 99: 1540-1547 93 | 302 patients (89% men) with chronic CAD (previous MI, bypass surgery, or >50% angiographic stenosis of ≥1 major coronary artery), >18 y, IgG anti-Chlamydia pneumoniae titer ≥1:16 | 3 mo of azithromycin treatment (500 mg/d for 3 days then 500 mg/wk) vs placebo; follow-up, 6 mo |
| Clinical cardiovascular events at 6 mo did not differ between groups; azithromycin reduced a global rank sum score of 4 inflammatory markers (C-reactive protein, interleukin 1, interleukin 6, tumor necrosis factor α; P=.01) at 6 (but not 3) mo; C pneumoniae IgG and IgA antibody titers were unchanged |
| ACES 94 | 4000 patients with stable CAD (previous MI, bypass surgery, or >50% angiographic stenosis of ≥1 major coronary artery, revascularization) | Azithromycin, 600 mg/wk for 1 y vs placebo; follow-up, 4 y |
| Expected in 2004 |
| MARBLE, 95 London | 1240 patients with known CAD on waiting list for elective coronary artery bypass surgery randomized while waiting for surgery | Chronic antibiotic therapy in addition to concomitant antianginal medication | Primary: cardiovascular events | Expected in 2003 |
* ACADEMIC = Azithromycin in Coronary Artery Disease: Elimination of Myocardial Infection with Chlamydia; ACES = Azithromycin and Coronary Events Study; CAD = coronary artery disease; MARBLE = Might Azithromycin Reduce Bypass List Events?; MI = myocardial infarction.
In summary, no large randomized controlled trial has shown a significant reduction in cardiovascular events with short-term antibiotic treatment in patients with a history of chronic CAD and positive C pneumoniae titers; a possible benefit on inflammatory markers was suggested in one small trial.
Acute Coronary Syndromes
About one half of patients with acute coronary syndromes have positive C pneumoniae serology. Of necessity, all trials in such patients use the “blanket approach” and treat all patients irrespective of C pneumoniae serology.
The small ROXIS (Randomized Trial of Roxithromycin in Non-Q-Wave Coronary Syndromes) pilot trial suggested a possible benefit of roxithromycin (due to antimicrobial or anti-inflammatory effects) in patients with non-Q-wave coronary syndromes (Table 5). Because less than half of roxithromycin- or placebo-treated patients were seropositive (IgG anti-C pneumoniae titer ≥1:64) and no association was shown between the efficacy of roxithromycin and IgG titers, it is likely that roxithromycin's anti-inflammatory effects played a role.
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C-reactive protein, a marker of inflammation and a predictor of future cardiac events, differed in the 2 groups.102
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In those with a positive response, C-reactive protein levels decreased from 53.7% to 35.8% at day 31 in the roxithromycin group vs 47.4% to 31.3% in the placebo group (P=.03). Within an unstable atherosclerotic plaque, such attenuation of inflammation could result in a more stable state and fewer subsequent cardiovascular events. In support of this, patients with positive IgG titers and elevated C-reactive protein levels were more likely to experience a recurrent ischemic event than those with negative IgG titers and low C-reactive protein levels (43% vs 9%; P=.03).Table 5Randomized Controlled Trials of Antibiotics for Acute Coronary Syndromes
*
AZACS = Azithromycin in Acute Coronary Syndromes; CLARIFY = Clarithromycin in Acute Coronary Syndrome patients in Finland; MI = myocardial infarction; PROVE IT = Pravastatin or Atorvastatin Evaluation and Infection Therapy; ROXIS = Randomized Trial of Roxithromycin in Non-Q-Wave Coronary Syndromes; STAMINA = South Thames Trial of Antibiotics in Myocardial Infarction and Unstable Angina.
| Trial | Study population | Treatment | End point | Results |
|---|---|---|---|---|
| AZACS 96 | 1439 patients (74% men) enrolled shortly after admission for acute coronary syndrome. 826 of whom had acute MI | Azithromycin (single dose of 500 mg followed by 4 days of 250 mg initiated 3-4 days after admission) vs placebo; follow-up, 6 mo | Primary (composite): death, cardiac arrest, nonfatal MI, and revascularization | No significant difference in composite primary end point (12.6% in placebo vs 12.3% in azithromycin group; P=NS) |
| Secondary: unstable angina, congestive heart failure | ||||
| CLARIFY 97 | 148 patients (70% men), 105 with non-Q-wave MI and 43 with unstable angina | Clarithromycin (500 mg/d) for 85 days vs placebo | Primary (composite): death, MI, or unstable angina | No significant difference in primary end point within 3 mo (19 events in placebo vs 11 events in clarithromycin group; P=. 10); significant difference in secondary end point throughout mean follow-up (median, 555 days): 27 events in placebo vs 16 events in clarithromycin group, risk ratio, 0.49; P=.03 |
| Secondary: death, MI, unstable angina, ischemic stroke, and critical limb ischemia | ||||
| ROXIS, 98 Argentina | 202 patients (76% men) with unstable angina from 8 coronary care units; age >21 y | Roxithromycin (150 mg twice daily) for 30 days vs placebo; follow-up, 6 mo | Primary (composite): cardiac ischemic death, MI, severe recurrent ischemia Secondary: anti-Chlamydia pneumoniae IgG titers, C-reactive protein | Day 30: the primary triple end point rates were 9% in placebo vs 2% in roxithromycin group (P=.03) Day 90: 12.5% vs 4.37%, respectively (P=.06) Day 180: 14.6% vs 8.69%, respectively (P=.26) |
| PROVE IT 99 | 4000 patients with acute coronary syndrome for <10 days and a total cholesterol level of 150-240 mg/dL | 2 by 2 factorial trial of pravastatin vs atorva-statin and gatifloxacin (400 mg/d for 10 days, then 10 days per month for trial duration) vs placebo; follow-up, 2 y | Primary: death, MI, stroke, hospitalization for angina, revascularization Secondary: lipid levels, high-sensitivity C-reactive protein, anti-C pneumoniae IgG titers | Expected in 2005 |
| Single-center trial, 100 Siriraj Hospital | 84 patients with acute coronary syndrome admitted to a single hospital in Bangkok. Thailand | Roxithromycin (150 mg twice daily) for 30 days vs placebo; follow-up, 90 days | Primary: cardiac death, unplanned revascularization, recurrent angina/Ml | No significant difference in cardiac events (17 in roxithromycin vs 16 in placebo group); anti-C pneumoniae IgG positivity was 55.8% in roxithromycin vs 56.1% in placebo group |
| Secondary: anti-C pneumoniae titers (IgG and IgA) | ||||
| STAMINA 101
Effect of treatment for Chlamydia pneumoniae and Helicobacter pylori on markers of inflammation and cardiac events in patients with acute coronary syndromes: South Thames Trial of Antibiotics in Myocardial Infarction and Unstable Angina (STAMINA). Circulation. 2002; 106: 1219-1223 | 324 patients from 4 hospitals in south London admitted with an acute coronary syndrome (MI or unstable angina) | Antibiotics given during hospitalization: azithromycin, metronidazole, and omeprazole; amoxicillin, metronidazole, and omeprazole; or placebo; follow-up, 1 y | Primary: unstable angina or MI | Patients who received antibiotic therapy with either azithromycin or amoxicillin had a 40% reduction in unstable angina or MI |
| Secondary: antibodies to C pneumoniae and Helicobacter pylori |
* AZACS = Azithromycin in Acute Coronary Syndromes; CLARIFY = Clarithromycin in Acute Coronary Syndrome patients in Finland; MI = myocardial infarction; PROVE IT = Pravastatin or Atorvastatin Evaluation and Infection Therapy; ROXIS = Randomized Trial of Roxithromycin in Non-Q-Wave Coronary Syndromes; STAMINA = South Thames Trial of Antibiotics in Myocardial Infarction and Unstable Angina.
† Pilot trial.
The small single-center study at Siriraj Hospital in Bangkok used the same protocol as ROXIS and found no significant difference in events at 90 days (Table 5).
The AZACS (Azithromycin in Acute Coronary Syndromes) trial enrolled 1439 patients (74% men) shortly after admission for acute coronary syndrome.
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After a brief course of azithromycin vs placebo, no significant difference was noted in composite primary end point (death, cardiac arrest, nonfatal MI, and revascularization) (12.6% in placebo group vs 12.3% in azithromycin group; P=NS) or in any of its components. Also, there was no difference in rates of end points in patients enrolled with acute MI or with antibodies to C pneumoniae (Table 5).CLARIFY (Clarithromycin in Acute Coronary Syndrome patients in Finland) treated patients with non-Q-wave MI or unstable angina with clarithromycin or placebo for 85 days and found a trend toward reduced primary end point events (death, MI, or unstable angina) at 3 months.
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When all cardiovascular events were included (secondary end point), there was a significant reduction in events, beginning at the 3-month period and continuing until about 10 months, then remaining approximately the same thereafter (Table 5). Compared to ROXIS, CLARIFY had more patients with first-time angina and fewer patients with previous MI or revascularizations; however, the patients’ condition was more unstable, with the number of events during the first 3 months in the placebo groups being higher (26% in CLARIFY vs 13% in ROXIS). CLARIFY suggests that the beneficial effect starts during the treatment phase (3 months) and continues for at least another 7 months (continued separation of event curves).In STAMINA (South Thames Trial of Antibiotics in Myocardial Infarction and Unstable Angina), the antibiotics selected (triple therapy analogous to that used to eradicate H pylori in gastric ulcers) were aimed at controlling infection by both C pneumoniae and H pylori (Table 5). The surprising finding in this small study was that the antibiotics produced beneficial effects whether or not the patient was a carrier of one or both infections. This suggests that the antibiotics may be working either against a different infection or in an alternative manner.
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- Stone AF
- Mendall MA
- Kaski JC
- et al.
Effect of treatment for Chlamydia pneumoniae and Helicobacter pylori on markers of inflammation and cardiac events in patients with acute coronary syndromes: South Thames Trial of Antibiotics in Myocardial Infarction and Unstable Angina (STAMINA).
Circulation. 2002; 106: 1219-1223
PROVE IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) is a well-powered study (N=4000) examining long-term use of gatifloxacin in patients presenting with an acute coronary syndrome and elevated cholesterol levels; results are expected in 2005 (Table 5).
In summary, in patients with acute coronary syndromes, no large well-powered randomized controlled trial has been completed. Results of available trials have been mixed. Two small trials showed benefit on total cardiovascular events (ROXIS, CLARIFY); one small pilot trial showed a decrease in events with several triple therapeutic antibiotic regimens (STAMINA).
POSSIBLE EXPLANATIONS FOR STUDY RESULTS
Period of Antibiotic Treatment Too Brief
The main reason that the previously mentioned studies did not extend azithromycin therapy beyond a few months is that safety and efficacy data on long-term treatment are lacking. Long-term administration may be required to exert chronic anti-C pneumoniae, anti-inflammatory, or other effects beneficial to plaque remodeling and stabilization. This may be analogous to the anti-inflammatory effects of statins, which lead to greater divergence of treatment and placebo event curves over the long term.
AZACS used treatment for only 5 days, and patients in WIZARD received azithromycin once weekly for 3 months; neither trial showed a significant cardiovascular effect. In AZACS, a small, early separation of time-to-event curves was visually apparent, but the curves came together and then crossed 2 months after the 4-day treatment course ended.
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In addition, in WIZARD, a secondary treatment-by-time analysis at 6 months showed a significant reduction of 33% in the secondary end point of death or MI (relative risk, 0.67; 95% CI, 0.48-0.94).96
Thus, AZACS and WIZARD support an early benefit after treatment in the risk of MI and a possible waning of effect once the active treatment is discontinued. This would be consistent with a cytostatic rather than a cytocidal effect of the short course of the antibiotic.
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In the small ROXIS pilot trial (treatment period 1 month), there was a decrease in the triple end point at 1 month, which became nonsignificant as time advanced after the last antibiotic dose. Roxithromycin, a second-generation macrolide used in ROXIS, may have differing effects on inflammation than other macrolides.75
In addition, reinfection by C pneumoniae (eg, from peripheral monocytes containing viable C pneumoniae) during the antibiotic-free follow-up period may have led to further infection, inflammation, and instability of the plaque by C pneumoniae and thus excess cardiac events.98
CLARIFY supports the notion that benefits occur during the treatment phase, which was longer than that in ROXIS (3 months vs 1 month), but also for several months after the treatment phase is completed. The survival curves separated further as the treatment phase continued, again supporting the hypothesis that a longer duration of antibiotic treatment is necessary.
After 3 months of treatment in ACADEMIC (a small trial), there was no significant effect on cardiovascular primary end points; however, there was a significant improvement in inflammatory markers at 6 months but not at 3 months. This suggests that a longer duration of treatment may result in greater anti-inflammatory effects; there also may be a lag effect of antibiotic treatment on subsequent inflammation.
Two large studies are treating patients with antibiotics for a longer period: 1 year of azithromycin (a macrolide) in ACES and 2 years of gatifloxacin (a quinolone) in PROVE IT. These trials will test the hypothesis that long-term antibiotic treatment decreases cardiovascular events.
C pneumoniae Antibody Titers May Be Misleading
As discussed earlier, all serologic tests are not equal, and many uncertainties still exist regarding the meaning of anti-C pneumoniae IgG titers. Of the clinical trials, WIZARD found that titer levels had no effect on outcome. Intervention with antibiotics did not affect titer levels in ACADEMIC or ROXIS, and cardiac events or anti-inflammatory effects occurred independent of anti-C pneumoniae IgG titers in ACADEMIC and STAMINA. Another pilot study (of patients who had undergone percutaneous transluminal coronary angioplasty) of 1 month of azithromycin treatment (8 g) found no effect on anti-C pneumoniae antibody titers.
106
These studies suggest that IgG titers may be an inadequate marker for guiding treatment.107
In a study of acute ischemic heart disease, PCR detected C pneumoniae DNA in peripheral blood mononuclear cells in 26% of patients (24/93) vs 5% of healthy subjects (2/42) (P=.008) and anti-C pneumoniae IgG in 76% vs 45% (P<.001), respectively.
108
A study of 95 patients with angiographically confirmed CAD and 104 healthy volunteers detected C pneumoniae DNA in peripheral blood mononuclear cells in 17% and 1%, respectively (odds ratio, 20.86; 95% CI, 2.71-160.67; P<.001).109
Both studies showed no correlation between anti-C pneumoniae antibody titers and positive PCR results for C pneumoniae DNA in peripheral blood mononuclear cells. Viable C pneumoniae has been cultured from peripheral blood mononuclear cells.16
Of note, PCR assays for C pneumoniae are still being refined.110
These results raise the question, “Does detection of C pneumoniae in peripheral blood mononuclear cells aid in selecting which patients may benefit from antibiotics?”CONCLUSION
The potential role of C pneumoniae in coronary atherosclerosis may be more related to acceleration of disease or systemic effects by persistent infection than to sudden initiation of infarction by acute infection.
111
Whether patients with CAD or acute coronary syndromes benefit from antibiotics is an evolving issue. Short-term antibiotic treatment in patients with CAD and positive C pneumoniae serology does not significantly decrease cardiovascular events. One robust study (ACES) should determine whether long-term treatment is required to decrease cardiac events.Several small trials have suggested that treating acute coronary syndromes with antibiotics may be beneficial, regardless of C pneumoniae serology. A large well-powered trial (PROVE IT) with long-term antibiotic treatment may shed light on this subject.
A proposed model for C pneumoniae, antibiotics, and CAD based on the available data is as follows. C pneumoniae infection may have a direct noxious effect on the arterial wall, which may initiate and accelerate the atherosclerotic process. Alternatively, C pneumoniae may induce other inflammatory, oxidant, or thrombotic factors. Antibiotics (eg, macrolides, quinolones, tetracyclines, or anti-tuberculars) may affect CAD through their antichlamydial action (bacteriostatic or bacteriocidal), through other factors (anti-inflammatory, antioxidant, or antithrombotic), via a direct effect, or some combination of these. Vaccination before initial exposure may be the best approach, and the vaccine TWARVAX (AntexBiologics Inc, Gaithersburg, Md) is being actively investigated. In producing this vaccine, functional genomics were used, and a family of novel proteins in C pneumoniae were cloned and expressed recombinantly. TWARVAX is currently being evaluated in preclinical models as a potential subunit vaccine to treat and prevent chronic C pneumoniae infection.
112
TWARVAX. Gaithersburg, Md: Antex Biologics Inc. Available at: www.antexbiologics.com/antexbio/twarvax.phtm. Accessibility verified January 15, 2003.
At this time, several points are clear. (1) C pneumoniae serology by itself does not assist in identifying persons who might benefit from antibiotic treatment. This serology in combination with inflammatory markers may have better predictive value. (2) Anti-inflammatory effects are clearly manifesting in patients treated with macrolides and may be the conduit through which the benefits are occurring. (3) Combinations of antibiotics, including triple therapy, may be superior to single antibiotic therapy. (4) A longer duration of antibiotic therapy is probably important in providing continued bactericidal-cytocidal (rather than cytostatic) and anti-inflammatory effects. (5) Overall pathogen burden is probably important in inflammation and atherosclerosis, and pilot studies of antibiotic strategies (eg, triple therapy) against several pathogens appear to be effective.
39
, 113
, 114
Until well-designed and powered ongoing studies of long-term treatment prove a significant benefit, antibiotic treatment of patients with acute or chronic CAD cannot be recommended.
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