Original Article
Antibiotic Treatment of Chlamydia pneumoniae after Acute Coronary Syndrome
N Engl J Med 2005; 352:1646-1654April 21, 2005
- Abstract
Background
Chlamydia pneumoniae has been found within atherosclerotic plaques, and elevated titers of antibody to this organism have been linked to a higher risk of coronary events. Pilot studies have suggested that antibiotic treatment may reduce the risk of cardiovascular events.
Methods
We enrolled 4162 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and evaluated the efficacy of long-term treatment with gatifloxacin, a bactericidal antibiotic known to be effective against C. pneumoniae, in a double-blind, randomized, placebo-controlled trial. Subjects received 400 mg of gatifloxacin daily during an initial 2-week course of therapy that began 2 weeks after randomization, followed by a 10-day course every month for the duration of the trial (mean duration, 2 years), or placebo. The primary end point was a composite of death from all causes, myocardial infarction, documented unstable angina requiring rehospitalization, revascularization (performed at least 30 days after randomization), and stroke.
Results
A Kaplan–Meier analysis revealed that the rates of primary-end-point events at two years were 23.7 percent in the gatifloxacin group and 25.1 percent in the placebo group (hazard ratio, 0.95; 95 percent confidence interval, 0.84 to 1.08; P=0.41). No benefit was seen in any of the prespecified secondary end points or in any of the prespecified subgroups, including patients with elevated titers to C. pneumoniae or C-reactive protein.
Conclusions
Despite long-term treatment with a bactericidal antibiotic effective against C. pneumoniae, no reduction in the rate of cardiovascular events was observed.
Media in This Article
Figure 1
Numbers of Patients Who Were Randomly Assigned to a Treatment Group, Who Started the Assigned Treatment, and Who Discontinued Treatment or Were Lost to Follow-up.Figure 2
Kaplan–Meier Estimates of Events over Time among Patients Treated with Gatifloxacin or Placebo.Article Activity
- Article
Although epidemiologic studies have identified numerous risk factors for atherosclerosis, many patients do not exhibit such risk factors, and this has prompted a search for additional contributors to the progression of the disease.1 Infection with various pathogens has been implicated in the development of coronary artery disease. Specifically, Chlamydia pneumoniae has been associated with a doubling of the risk of atherosclerosis or myocardial infarction.2-7 The organism has been detected in human atheroma,5,6 and animal models have shown that new infection with C. pneumoniae results in more extensive atherosclerosis.7-10 Although not all studies show a significant relationship between IgG titers to C. pneumoniae and coronary events, a meta-analysis of more than 20 studies suggests that such a relationship does exist.11
Given the potential etiologic relationship between C. pneumoniae and cardiac events, there has been great interest in the treatment of patients who have coronary artery disease with antibiotics that are effective against chlamydia. The results of some initial pilot trials were promising,12,13 but more recent, larger studies have shown mixed results.14-17 In the largest study, patients were treated with azithromycin, a bacteriostatic antibiotic, for three months. Although no benefit was seen after a mean duration of 2.5 years of follow-up, a reduction in the rate of death or myocardial infarction was seen at 6 months,15 suggesting that long-term treatment with antibiotics might be effective in the prevention of cardiovascular events. In addition, because C. pneumoniae has a unique life cycle that includes a long, dormant intracellular phase, long-term treatment would allow better potential eradication of this organism from the vasculature.
Accordingly, the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction (PROVE IT–TIMI) 22 trial was set up as a two-by-two factorial design to compare long-term treatment with gatifloxacin with that of placebo for the prevention of death or major cardiovascular events in patients who had recently had an acute coronary syndrome. The study also compared standard and intensive statin therapy for the reduction of low-density lipoprotein cholesterol; the results of that comparison have been previously reported.18 Gatifloxacin is a quinolone antibiotic with bactericidal activity against C. pneumoniae and has been shown to prevent atherosclerosis in an animal model.19
Methods
Patients
As previously described, between November 15, 2000, and December 22, 2001, 4162 patients underwent randomization at 349 sites in eight countries.18 Men and women who were at least 18 years of age were eligible for inclusion if they had been hospitalized for an acute coronary syndrome — either acute myocardial infarction (with or without electrocardiographic evidence of ST-segment elevation) or high-risk unstable angina — within the preceding 10 days. Patients had to be in stable condition and were to be enrolled after a percutaneous revascularization procedure if one had been planned. Exclusion criteria were as previously reported.18 The protocol was approved by the relevant institutional review boards, and written informed consent was obtained from all patients.
Study Protocol
The protocol specified that patients receive standard medical and interventional treatment, including aspirin at a dose of 75 to 325 mg daily, with or without clopidogrel or warfarin, for acute coronary syndromes. Eligible patients underwent randomization in a 1:1 ratio to receive 400 mg of gatifloxacin daily or placebo, to be administered in a double-blind fashion. Subjects in the gatifloxacin group received an initial 2-week course of therapy beginning at the visit on day 15, followed by a 10-day course every month for the duration of the trial. The duration of follow-up ranged from 18 to 32 months, with a mean duration of 2 years. In addition, in a two-by-two factorial design, as previously reported,18 patients also underwent randomization to receive 40 mg of pravastatin or 80 mg of atorvastatin daily.
Patients were seen for follow-up visits at 30 days, 4 months, and every 4 months thereafter until a final visit in August or September of 2003. Patients who discontinued treatment with the study drug during the trial were followed by telephone contact. Blood samples for the measurement of antibodies to C. pneumoniae were obtained at baseline, at 4 months, and at the final visit and underwent assay at a central core laboratory; samples for the assay (by Denka Seiken) for high-sensitivity C-reactive protein were obtained at these times and also at 30 days. In a substudy at selected centers, blood samples were obtained at baseline and at four months for assessment by polymerase chain reaction for the presence of DNA of C. pneumoniae.
The dosage of the study drug could be reduced to a five-day course per month if patients had symptoms of drug intolerance, including diarrhea or nausea. The trial continued until reports of 925 events had been received at the coordinating center, after which all patients were asked to return for a final visit. Eight patients (0.2 percent) were lost to follow-up (Figure 1Figure 1
Numbers of Patients Who Were Randomly Assigned to a Treatment Group, Who Started the Assigned Treatment, and Who Discontinued Treatment or Were Lost to Follow-up.).20 End Points
The measure of the primary efficacy outcome was the time from randomization until the first occurrence of a component of the primary end point — death from all causes, myocardial infarction, documented unstable angina that required rehospitalization, revascularization with either percutaneous coronary intervention or coronary-artery bypass surgery (if these procedures were performed at least 30 days after randomization), or stroke; the definitions of these events have been previously reported.18 Secondary end points were the risk of death from coronary heart disease, nonfatal myocardial infarction, or revascularization (if performed at least 30 days after randomization) and the risk of death from coronary heart disease or of nonfatal myocardial infarction, as well as the individual components of the primary end point. Prespecified subgroup analyses were performed among patients with elevated C. pneumoniae antibody titers and according to quintiles of C-reactive protein levels at baseline as well as sex, smoking status, and the presence or absence of diabetes mellitus.
Statistical Analysis
We compared the results of treatment with gatifloxacin with those of placebo using Kaplan–Meier analyses of event rates as well as Cox proportional-hazards ratios over the duration of follow-up. On the assumption that there would be a two-year event rate of 24 percent in the placebo group during an average of two years of follow-up, a total of 2000 patients per group was considered necessary to yield 925 primary end points and give the study 94 percent power to detect a 19 percent reduction in the primary end point. This was based on a hypothesis that treatment with antibiotics would lead to a 20 percent reduction in events; however, because we were starting treatment with the drug on day 15, and no benefit could be derived before this, a 19 percent overall reduction of risk would be expected. Allocation of treatment was based on a central randomization system in which treatment was assigned according to the method of randomized permuted blocks of patients, stratified according to center. Two interim assessments of efficacy and safety were carried out by an independent data and safety monitoring board. Rules for early cessation due to the superiority of either treatment were not prespecified.
All efficacy analyses were based on the intention-to-treat principle. Estimates of hazard ratios and associated 95 percent confidence intervals for the comparison of gatifloxacin with placebo were obtained with the Cox proportional-hazards model, with randomized treatment as the covariate and stratification according to statin group. With the two-by-two factorial design, a test for interaction with statins was carried out, and no interaction was found with the groups receiving treatment with statins. The investigators designed the trial and had free and complete access to the data. The study was designed by the TIMI Study Group. Data coordination was performed by the Nottingham Clinical Research Group.18 Investigators from TIMI, the sponsor, and Nottingham performed data analysis jointly, and all groups vouch for the data.
Results
The two groups of enrolled patients were similar (Table 1Table 1
Baseline Characteristics of the Patients.). Their average age was 58 years, and 22 percent were women. Before their index event, 38 percent of patients had evidence of previous cardiovascular disease, and 18 percent had diabetes mellitus. As their index event, approximately one third had high-risk unstable angina, one third had myocardial infarction associated with electrocardiographic ST-segment elevation, and one third had myocardial infarction without such elevation. Sixty-nine percent of patients had undergone percutaneous coronary intervention for treatment of their index acute coronary syndrome before randomization. Concomitant medications were administered to patients during the treatment period as follows: aspirin, 93 percent; warfarin, 8 percent; clopidogrel or ticlodipine, 72 percent initially and 20 percent at one year; beta-blockers, 85 percent; angiotensin-converting–enzyme (ACE) inhibitors, 69 percent; and angiotensin-receptor blockers, 14 percent. The study drug was administered for an average of 1.6 years in the gatifloxacin group and 1.7 years in the placebo group. By one year, 74.4 percent of patients in the gatifloxacin group and 80.0 percent of those in the placebo group were taking the study drug. There were 3025 and 3272 patient-years of exposure to gatifloxacin and placebo, respectively.For all randomized patients, Kaplan–Meier estimates of the event rates for the primary end point at two years were 23.7 percent in the gatifloxacin group and 25.1 percent in the placebo group (Figure 2Figure 2
Kaplan–Meier Estimates of Events over Time among Patients Treated with Gatifloxacin or Placebo.), representing a hazard ratio of 0.95 (95 percent confidence interval, 0.84 to 1.08; P=0.41). The risk associated with the secondary end point of death due to coronary heart disease, myocardial infarction, or revascularization also was not significantly reduced among patients receiving gatifloxacin, with a rate of 20.4 percent as compared with 21.6 percent among those receiving placebo (hazard ratio, 0.95; 95 percent confidence interval, 0.84 to 1.09; P=0.48). The risk of death due to coronary heart disease or myocardial infarction was also not significantly reduced in the gatifloxacin group, at 7.6 percent as compared with 8.0 percent in the placebo group (hazard ratio, 0.97; P=0.78). There was no reduction in the individual components of the primary end point among patients treated with gatifloxacin (Figure 3Figure 3
Risk Reduction for Death or a Major Cardiovascular Event and Event Rates at Two Years.).No benefit from gatifloxacin was observed among prespecified clinical subgroups in terms of either the primary end point (Figure 4Figure 4
Hazard Ratios for Death or a Major Cardiovascular Event, with Two-Year Event Rates, According to Baseline Characteristics.) or the secondary end point of death from coronary heart disease or myocardial infarction (data not shown). Testing of baseline IgG antibody titers to C. pneumoniae did not identify a subgroup of patients who benefited from antibiotic treatment (Figure 4), including the 5 percent of patients who had the highest baseline titers (greater than 1:512) (data not shown). There was no effect of gatifloxacin on antibody titers over the trial period. In the placebo group, there was a decrease in antibody titers over time, with the percentage of patients in whom titers were elevated falling from 64.6 percent at baseline to 52.4 percent at the final visit (P<0.001). An identical pattern was seen in the gatifloxacin group, with a fall from 64.0 percent at baseline to 53.5 percent at the final visit (P<0.001). The P value for interaction was not significant, and thus treatment with gatifloxacin did not influence antibody titers to C. pneumoniae. In the substudy that assessed the presence of DNA for C. pneumoniae in peripheral mononuclear blood cells, only 6 of 171 patients in the placebo group (3.5 percent) and 6 of 172 in the gatifloxacin group (3.5 percent) were positive at baseline. At four months, among 80 patients who received gatifloxacin and 89 who received placebo with follow-up blood samples, 3 (3.8 percent) and 4 (4.5 percent), respectively, were positive (P not significant).Use of levels of C-reactive protein at baseline to define subgroups according to either the median level of 12.1 mg per liter (Figure 4) or according to quintile did not identify any subgroups that had a benefit from gatifloxacin. Over the duration of the trial, there were no differences in achieved C-reactive protein levels between patients receiving gatifloxacin and those receiving placebo; in each group, the level was 1.7 mg per liter at four months and 1.8 mg per liter at the final visit (P not significant for either time).
Tolerability and Safety
As expected, the side effects of diarrhea and nausea or vomiting associated with antibiotic treatment were significantly more common among patients receiving gatifloxacin (8.1 percent had diarrhea, and 7.3 percent nausea or vomiting; P=0.01) than among those receiving placebo (6.1 percent and 5.5 percent, respectively; P=0.02). Slight changes in blood glucose levels were noted in the gatifloxacin group, as previously reported with this agent.21 Among patients who did not have diabetes mellitus at baseline, new-onset diabetes (defined as the presence of one or more nonfasting serum glucose values of ≥200 mg per deciliter, two or more nonfasting serum glucose values of ≥140 mg per deciliter, or two or more fasting serum glucose values of ≥126 mg per deciliter) tended to develop more frequently in patients treated with gatifloxacin than in those given placebo (4.6 percent vs. 3.4 percent, P=0.08). Among patients with diabetes, there were trends toward more patients who were treated with gatifloxacin having episodes of hyperglycemia than patients who were treated with placebo (30.7 percent vs. 25.4 percent, P=0.11) and toward more patients who were treated with gatifloxacin having episodes of hypoglycemia (2.6 percent vs. 1.5 percent, P=0.32). Conversely, fewer upper respiratory tract infections developed in patients receiving the monthly courses of gatifloxacin than in patients receiving placebo (10.9 percent vs. 14.8 percent, P<0.001), and fewer sinus infections developed in patients in the gatifloxacin group than in those in the placebo group (4.6 percent vs. 6.5 percent, P=0.01).
Discussion
Although there is evidence to suggest that C. pneumoniae has a role in the development of atherosclerosis, we were not able to detect a benefit from long-term antibiotic therapy in patients who had recently been hospitalized for an acute coronary syndrome. These results are in agreement with those of Grayston et al., reported elsewhere in this issue of the Journal.22 There was no reduction in the primary end point, the secondary end points, or any of the individual components of the primary end point as a result of antibiotic treatment. None of the prespecified subgroups, distinguished by high-risk clinical characteristics, C-reactive protein levels, antibody titers to C. pneumoniae, or the presence of C. pneumoniae within peripheral mononuclear blood cells, showed any benefit from the antibiotic treatment. Thus, our findings suggest that for patients who have had a recent acute coronary syndrome and who have established cardiovascular disease, antibiotic therapy is not effective in reducing the risk of recurrent cardiovascular events. When these findings are juxtaposed with the significant benefit of intensive statin therapy as compared with standard statin therapy that was observed in the same trial,18 the results reinforce the importance of using proven therapies for secondary prevention in this population.
Our trial differed from prior studies of antibiotics12-17 in that it involved a large number of high-risk patients with acute coronary syndromes, among whom more than 1000 primary end points were observed; the trial thus had a more than 97 percent power to detect (or rule out) a benefit from antibiotic treatment of 19 percent and an 85 percent power to detect (or rule out) a benefit of 17 percent. In addition, we continued antibiotic treatment longer than any of the prior trials, using monthly courses of therapy throughout the two-year duration of the trial. We studied patients with acute coronary disease, the severity of which, it had been thought, would allow C. pneumoniae to be potentially active within coronary lesions. Finally, full-dose gatifloxacin, a bactericidal quinolone antibiotic known to be destructive to C. pneumoniae, was used, in contrast to the bacteriostatic macrolide antibiotics that were used in prior studies. Despite the long-term, full-dose antibiotic treatment, no reduction in cardiac events was observed with antibiotic treatment in patients who had recently been hospitalized for an acute coronary syndrome.
In determining the potential reasons why antibiotic treatment was not effective, we assessed disease activity in several ways. The substudies point to an absence of active infection in the middle-aged patients with established coronary disease who were enrolled. With the use of serial antibodies to C. pneumoniae, no increase in titers was observed, as would be expected if patients had active infection with the organism. These findings were supported by the substudy that found that only 4 percent of patients had evidence of C. pneumoniae in their mononuclear blood cells (a marker that has been shown in other studies to be well correlated with the presence of C. pneumoniae in arterial plaque).2,23 Finally, there was no effect of antibiotic treatment on levels of C-reactive protein, a marker of inflammation, which might have been elevated by C. pneumoniae. Thus, the overall clinical results and the results of the three substudies within the trial suggest that patients were not actively infected with C. pneumoniae and that, accordingly, antibiotic therapy had no detectable effect.
Because the serologic and pathological evidence supports the likelihood of prior infection and the presence of C. pneumoniae within arterial plaque, it is possible that infection with C. pneumoniae is part of the initiation of atherosclerosis in the early decades of life but not an active part of the progression of disease later, when patients have established coronary artery disease. Indeed, the animal model that has shown a benefit of antibiotic therapy with either azithromycin or gatifloxacin is that of cholesterol-fed rabbits, in which antibiotic treatment at the time of initial infection can reduce the development of atherosclerosis.7,19 No model of established vascular disease has been used to show that the use of antibiotics reverses or slows the progression of the disease. The situation may be similar to that of other infections such as those involving the Epstein–Barr virus, which is a well-established cause of Burkitt's lymphoma. However, among patients in whom the lymphoma develops, treatment is not with antiviral agents but, rather, with chemotherapeutic agents. Thus, it is possible that C. pneumoniae is a cause of early atherosclerosis but that once the process is established, with the appearance of cholesterol-laden plaque and inflammation, therapy with antichlamydial antibiotics is not effective.
Accordingly, the two components of the PROVE IT–TIMI 22 trial highlight the proven benefit of intensive statin therapy after acute coronary syndromes, as recently advocated in an update to the guidelines of the National Cholesterol Education Program.24 Efforts toward secondary prevention in patients with these syndromes should be aimed at proven therapies, including antiplatelet therapy, treatment with beta-blockers and ACE inhibitors, and intensive lowering of lipid levels with the use of statins.
Supported by Bristol-Myers Squibb and Sankyo.
Dr. Cannon reports having received grant support from AstraZeneca, Bristol-Myers Squibb, Merck, and Sanofi–Aventis and having served on paid advisory boards for AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Sanofi–Aventis, and the Merck–Schering-Plough partnership. Dr. Braunwald reports having received grant support from Sanofi–Aventis and Bristol-Myers Squibb. Ms. McCabe reports having received grant support from AstraZeneca, Sanofi–Aventis, and Bristol-Myers Squibb. The Azithromycin and Coronary Events Study, for which Dr. Grayston was the principal investigator, received partial grant support from Pfizer. Dr. Muhlestein reports having received grant support from and having served on paid advisory boards for Bristol-Myers Squibb. Dr. Giugliano reports having received lecture fees from Bristol-Myers Squibb.
Source Information
From the Thrombolysis in Myocardial Infarction Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston (C.P.C., E.B., C.H.M., R.P.G.); the Department of Epidemiology, University of Washington, Seattle (J.T.G.); LDS Hospital, Salt Lake City (B.M.); and Nottingham Clinical Research Group, Nottingham, United Kingdom (R.C., A.M.S.).
Address reprint requests to Dr. Cannon at the TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115, or at cpcannon@partners.org.
- References
References
1
Libby P ,Ridker PM ,Maseri A . Inflammation and atherosclerosis. Circulation 2002;105:1135-1143
CrossRef | Web of Science | Medline2
Danesh J ,Collins R ,Peto R . Chronic infection and coronary heart disease: is there a link? Lancet 1997;350:430-436
CrossRef | Web of Science | Medline3
Libby P ,Egan D ,Skarlatos S . Roles of infectious agents in atherosclerosis and restenosis: an assessment of the evidence and need for future research. Circulation 1997;96:4095-4103
Web of Science | Medline4
Kuo CC ,Shor A ,Campbell LA ,Fukushi H ,Patton DL ,Grayston JT . Demonstration of Chlamydia pneumoniae in atherosclerotic lesions of coronary arteries. J Infect Dis 1993;167:841-849
CrossRef | Web of Science | Medline5
Muhlestein JB ,Hammond EH ,Carlquist JF , et al. Increased incidence of Chlamydia species within the coronary arteries of patients with symptomatic atherosclerotic versus other forms of cardiovascular disease. J Am Coll Cardiol 1996;27:1555-1561
CrossRef | Web of Science | Medline6
Kuo CC ,Grayston JT ,Campbell LA ,Goo YA ,Wissler RW ,Benditt EP . Chlamydia pneumoniae (TWAR) in coronary arteries of young adults (15-34 years old). Proc Natl Acad Sci U S A 1995;92:6911-6914
CrossRef | Web of Science | Medline7
Muhlestein JB ,Anderson JL ,Hammond EH , et al. Infection with Chlamydia pneumoniae accelerates the development of atherosclerosis and treatment with azithromycin prevents it in a rabbit model. Circulation 1998;97:633-636
Web of Science | Medline8
Fong IW ,Chiu B ,Viira E ,Fong MW ,Jang D ,Mahony J . Rabbit model for Chlamydia pneumoniae infection. J Clin Microbiol 1997;35:48-52
Web of Science | Medline9
Moazed TC ,Campbell LA ,Rosenfeld ME ,Grayston JT ,Kuo CC . Chlamydia pneumoniae infection accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice. J Infect Dis 1999;180:238-241
CrossRef | Web of Science | Medline10
Danesh J ,Whincup P ,Walker M , et al. Chlamydia pneumoniae IgG titres and coronary heart disease: prospective study and meta-analysis. BMJ 2000;321:208-213
CrossRef | Web of Science | Medline11
Danesh J ,Whincup P ,Walker M , et al. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ 2000;321:199-204
CrossRef | Web of Science | Medline12
Gupta S ,Leathan EW ,Carrington D ,Mendall MA ,Kaski JC ,Camm AJ . Elevated Chlamydia pneumoniae antibodies, cardiovascular events, and azithromycin in male survivors of myocardial infarction. Circulation 1997;96:404-407
Web of Science | Medline13
Gurfinkel E ,Bozovich G ,Daroca A ,Beck E ,Mautner B . Randomised trial of roxithromycin in non-Q-wave coronary syndromes: ROXIS Pilot Study. Lancet 1997;350:404-407
CrossRef | Web of Science | Medline14
Neumann F ,Kastrati A ,Miethke T , et al. Treatment of Chlamydia pneumoniae infection with roxithromycin and effect on neointima proliferation after coronary stent placement (ISAR-3): a randomised, double-blind, placebo-controlled trial. Lancet 2001;357:2085-2089
CrossRef | Web of Science | Medline15
O'Connor CM ,Dunne MW ,Pfeffer MA , et al. Azithromycin for the secondary prevention of coronary heart disease events: the WIZARD study: a randomized controlled trial. JAMA 2003;290:1459-1466
CrossRef | Web of Science | Medline16
Cercek B ,Shah PK ,Noc M , et al. Effect of short-term treatment with azithromycin on recurrent ischaemic events in patients with acute coronary syndrome in the Azithromycin in Acute Coronary Syndrome (AZACS) trial: a randomised controlled trial. Lancet 2003;361:809-813
CrossRef | Web of Science | Medline17
Zahn R ,Schneider S ,Frilling B , et al. Antibiotic therapy after acute myocardial infarction: a prospective randomized study. Circulation 2003;107:1253-1259
CrossRef | Web of Science | Medline18
Cannon CP ,Braunwald E ,McCabe CH , et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-1504
Full Text | Web of Science | Medline19
Jones HU ,Muhlestein JB ,Lim TH , et al. Short-term therapy with gatifloxacin or azithromycin prevents the acceleration of atherosclerosis after infection with Chlamydia pneumoniae in a rabbit model but does not eradicate the organism from plaque. J Am Coll Cardiol 2003;41:289A-289A abstract.
CrossRef | Web of Science20
Wang SP ,Kuo CC ,Grayston JT . Formalinized Chlamydia trachomatis organisms as antigen in the micro-immunofluorescence test. J Clin Microbiol 1979;10:259-261
Web of Science | Medline21
Gajjar DA ,LaCreta FP ,Kollia GD , et al. Effect of multiple-dose gatifloxacin or ciprofloxacin on glucose homeostasis and insulin production in patients with noninsulin-dependent diabetes mellitus maintained with diet and exercise. Pharmacotherapy 2000;20:76S-86S
CrossRef | Web of Science | Medline22
Grayston JT ,Kronmal RA ,Jackson LA , et al. Azithromycin for the secondary prevention of coronary events. N Engl J Med 2005;352:1637-1645
Full Text | Web of Science | Medline23
Juvonen J ,Juvonen T ,Laurila A , et al. Demonstration of Chlamydia pneumoniae in the walls of abdominal aortic aneurysms. J Vasc Surg 1997;25:499-505
CrossRef | Web of Science | Medline24
Grundy SM ,Cleeman JI ,Merz CNB , et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227-239
CrossRef | Web of Science | Medline
- Citing Articles (72)
Citing Articles
1
Lorne M. Golub, Robert A. Greenwald. (2011) Clinical applications of non-antibacterial tetracyclines. Part II. Pharmacological Research 64:6, 549-550
CrossRef2
Marcus B. Conde, José R. Lapa e Silva. (2011) New regimens for reducing the duration of treatment of drug-susceptible pulmonary tuberculosis. Drug Development Research 72:6, 501-508
CrossRef3
Zeneng Wang, Elizabeth Klipfell, Brian J. Bennett, Robert Koeth, Bruce S. Levison, Brandon DuGar, Ariel E. Feldstein, Earl B. Britt, Xiaoming Fu, Yoon-Mi Chung, Yuping Wu, Phil Schauer, Jonathan D. Smith, Hooman Allayee, W. H. Wilson Tang, Joseph A. DiDonato, Aldons J. Lusis, Stanley L. Hazen. (2011) Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472:7341, 57-63
CrossRef4
Carmen Gómez-Guerrero, Beñat Mallavia, Jesus Egido. (2011) Targeting Inflammation in Cardiovascular Diseases. Still a Neglected field?. Cardiovascular Therapeuticsno-no
CrossRef5
Giovanna Liuzzo, Alessandra Ciervo, Giampaolo Niccoli, Fabiola Mancini, Beatrice Fusco, Rocco A. Montone, Vincenzo Pazzano, Daniela Pedicino, Vincenzo A. Galiffa, Francesca Graziani, Luigi M. Biasucci, Rocco Mongiardo, Antonio Cassone, Filippo Crea. (2011) Chlamydia pneumoniae in coronary atherosclerotic plaques and coronary instability. International Journal of Cardiology 147:1, 176-178
CrossRef6
M. E. Rosenfeld, L. A. Campbell. (2011) Pathogens and atherosclerosis: Update on the potential contribution of multiple infectious organisms to the pathogenesis of atherosclerosis. Thrombosis and Haemostasis 106:5, 858-867
CrossRef7
Amir E. Zeituni, Julio Carrion, Christopher W. Cutler. (2010) Porphyromonas gingivalis –dendritic cell interactions: consequences for coronary artery disease. Journal of Oral Microbiology 2:0,
CrossRef8
P. M. Fitch, N. M. Wheelhouse, P. Bowles, M. Paterson, D. Longbottom, G. Entrican, S. E. M. Howie. (2010) Ectopic lymphoid tissue formation in the lungs of mice infected with Chlamydia pneumoniae is associated with epithelial macrophage inflammatory protein-2/CXCL2 expression. Clinical & Experimental Immunology 162:2, 372-378
CrossRef9
Justin F. Deniset, Grant N. Pierce. (2010) Possibilities for therapeutic interventions in disrupting Chlamydophila pneumoniae involvement in atherosclerosis. Fundamental & Clinical Pharmacology 24:5, 607-617
CrossRef10
Gregory J. Del Zoppo, Philip B. Gorelick. (2010) Innate inflammation as the common pathway of risk factors leading to TIAs and stroke. Annals of the New York Academy of Sciences 1207:1, 8-10
CrossRef11
Mitchell S. V. Elkind. (2010) Impact of innate inflammation in population studies. Annals of the New York Academy of Sciences 1207:1, 97-106
CrossRef12
Gorm B Jensen, Jørgen Hilden, Bodil Als-Nielsen, Morten Damgaard, Jørgen Fischer Hansen, Stig Hansen, Olav H Helø, Per Hildebrandt, Jens Kastrup, Hans Jørn Kolmos, Erik Kjøller, Inga Lind, Henrik Nielsen, Lars Petersen, Christian M Jespersen, Christian Gluud. (2010) Statin Treatment Prevents Increased Cardiovascular and All-Cause Mortality Associated With Clarithromycin in Patients With Stable Coronary Heart Disease. Journal of Cardiovascular Pharmacology 55:2, 123-128
CrossRef13
Shepard D. Weiner, LeRoy E. Rabbani. (2010) Secondary prevention strategies for coronary heart disease. Journal of Thrombosis and Thrombolysis 29:1, 8-24
CrossRef14
C. Chen, H. Chai, X. Wang, P. H. Lin, Q. Yao. (2009) Chlamydia heat shock protein 60 decreases expression of endothelial nitric oxide synthase in human and porcine coronary artery endothelial cells. Cardiovascular Research 83:4, 768-777
CrossRef15
F J. Nieto. (2009) Commentary: Understanding the pathophysiology of poverty. International Journal of Epidemiology 38:3, 787-790
CrossRef16
Claudio Napoli, Francesco Cacciatore. (2009) Novel Pathogenic Insights in the Primary Prevention of Cardiovascular Disease. Progress in Cardiovascular Diseases 51:6, 503-523
CrossRef17
Miquel Gómez, Vicente Valle, Fernando Arós, Ginés Sanz, Joan Sala, Miquel Fiol, Jordi Bruguera, Roberto Elosua, Lluís Molina, Helena Martí, M. Isabel Covas, Andrés Rodríguez-Llorián, Montserrat Fitó, Miguel A. Suárez-Pinilla, Rocío Amezaga, Jaume Marrugat. (2009) LDL oxidada, lipoproteína(a) y otros factores de riesgo emergentes en el infarto agudo de miocardio (estudio FORTIAM). Revista Española de Cardiología 62:4, 373-382
CrossRef18
Riitta Paakkanen, Anil Palikhe, Mikko Seppänen, Markku S. Nieminen, Hanna Vauhkonen, Pekka Saikku, Marja-Liisa Lokki, Juha Sinisalo. (2009) Beneficial effect of clarithromycin in patients with acute coronary syndrome and complement C4 deficiencies. Scandinavian Cardiovascular Journal 43:6, 395-401
CrossRef19
Tatjana Grdanoska. (2008) <i>Chlamydia pneumoniae</i> and Heart Desease. Macedonian Journal of Medical Sciences 1:2, 49-53
CrossRef20
M. HÖGDAHL, G. SÖDERLUND, E. KIHLSTRÖM. (2008) Expression of chemokines and adhesion molecules in human coronary artery endothelial cells infected with Chlamydia (Chlamydophila) pneumoniae . APMIS 116:12, 1082-1088
CrossRef21
Shaoshan S. Wang, A. Maziar Zafari. (2008) In search for a reliable assay to detect vascular infection with Chlamydia pneumoniae. International Journal of Cardiology 130:2, 262-263
CrossRef22
Turgay Celik, Atila Iyisoy, Murat Celik, Ersoy Isik. (2008) The ongoing debate over the association between Chlamydia pneumoniae infection and coronary artery disease: Antibiotic dilemma. International Journal of Cardiology 130:2, 260-261
CrossRef23
Enrique Villegas, Ana Camacho, Jose Antonio Carrillo, Antonio Sorlózano, José Rojas, José Gutiérrez. (2008) Emerging strategies in the diagnosis, prevention and treatment of Chlamydophila pneumoniae infections. Expert Opinion on Therapeutic Patents 18:10, 1175-1189
CrossRef24
Emmanouil S. Brilakis, James A. de Lemos, Christopher P. Cannon, Stephen D. Wiviott, Sabina A. Murphy, David A. Morrow, Marc S. Sabatine, Subhash Banerjee, Michael A. Blazing, Robert M. Califf, Eugene Braunwald. (2008) Outcomes of Patients With Acute Coronary Syndrome and Previous Coronary Artery Bypass Grafting (from the Pravastatin or Atorvastatin Evaluation and Infection Therapy [PROVE IT-TIMI 22] and the Aggrastat to Zocor [A to Z] Trials). The American Journal of Cardiology 102:5, 552-558
CrossRef25
Michelle Asha Albert. (2008) Race/Ethnicity and Inflammation – Is There a Link to Periodontal Disease?. Journal of Periodontology 79:7, 1121-1123
CrossRef26
Ignatios Ikonomidis, Kimon Stamatelopoulos, John Lekakis, Georgia D. Vamvakou, Dimitrios Th Kremastinos. (2008) Inflammatory and non-invasive vascular markers: The multimarker approach for risk stratification in coronary artery disease. Atherosclerosis 199:1, 3-11
CrossRef27
J J M Bouwman, F L J Visseren, K P Bouter, R J A Diepersloot. (2008) Infection-induced inflammatory response of adipocytes in vitro. International Journal of Obesity 32:6, 892-901
CrossRef28
Zhi Song, Paul Brassard, James M. Brophy. (2008) A meta-analysis of antibiotic use for the secondary prevention of cardiovascular diseases. Canadian Journal of Cardiology 24:5, 391-395
CrossRef29
Bojan Cercek. (2008) Increased Risk of Mortality following Antibiotic Treatment in Patients with Coronary Artery Disease?. Cardiology 111:4, 277-279
CrossRef30
Prediman K. Shah. 2008. Inflammation and atherothrombosis. , 1013-1021.
CrossRef31
Peter Andrew, Annibale Sandro Montenero. (2007) Is there a link between atrial fibrillation and certain bacterial infections?. Journal of Cardiovascular Medicine 8:12, 990-996
CrossRef32
Robert L Wilensky, Damir Hamamdzic. (2007) The molecular basis of vulnerable plaque: potential therapeutic role for immunomodulation. Current Opinion in Cardiology 22:6, 545-551
CrossRef33
Zhong-qun Yan, Göran K. Hansson. (2007) Innate immunity, macrophage activation, and atherosclerosis. Immunological Reviews 219:1, 187-203
CrossRef34
B. Piechowski-Jóźwiak, A. Mickielewicz, Z. Gaciong, H. Berent, H. Kwieciński. (2007) Elevated levels of anti-Chlamydia pneumoniae IgA and IgG antibodies in young adults with ischemic stroke. Acta Neurologica Scandinavica 116:3, 144-149
CrossRef35
Cynthia M. Westerhout, Judy Gnarpe, Wei-Ching Chang, Susan FitzPatrick, Elliot S. Barnathan, Eric Boersma, Robert M. Califf, Lars Wallentin, Maarten L. Simoons, Paul W. Armstrong. (2007) No prognostic significance of chronic infection with Chlamydia pneumoniae in acute coronary syndromes: Insights from the Global Utilization of Strategies to Open Occluded Arteries IV Acute Coronary Syndromes trial. American Heart Journal 154:2, 306-312
CrossRef36
Shaoshan S. Wang, Maria Lucia C. Tondella, Ambar Bajpai, Anil G. Mathew, Payam Mehranpour, Wei Li, Andro G. Kacharava, Barry S. Fields, Harland Austin, A. Maziar Zafari. (2007) Circulating Chlamydia pneumoniae DNA and advanced coronary artery disease. International Journal of Cardiology 118:2, 215-219
CrossRef37
M Mahmoudi, N Curzen, P J Gallagher. (2007) Atherogenesis: the role of inflammation and infection. Histopathology 50:5, 535-546
CrossRef38
I. Kardasz, R. De Caterina. (2007) Myocardial infarction with normal coronary arteries: a conundrum with multiple aetiologies and variable prognosis: an update. Journal of Internal Medicine 261:4, 330-348
CrossRef39
Javier Sanz, Pedro R Moreno, Valentin Fuster. (2007) Update on advances in atherothrombosis. Nature Clinical Practice Cardiovascular Medicine 4:2, 78-89
CrossRef40
G.L. Moneta. (2007) Antibiotic Treatment of Chlamydia pneumoniae after Acute Coronary Syndrome. Yearbook of Vascular Surgery 2007, 98-100
CrossRef41
Robyn Guymer, Luba Robman. (2007) Chlamydia pneumoniae and age-related macular degeneration: a role in pathogenesis or merely a chance association?. Clinical & Experimental Ophthalmology 35:1, 89-93
CrossRef42
Luigi Giusto Spagnoli, Sabina Pucci, Elena Bonanno, Antonio Cassone, Fabiola Sesti, Alessandra Ciervo, Alessandro Mauriello. (2007) Persistent Chlamydia pneumoniae Infection of Cardiomyocytes Is Correlated with Fatal Myocardial Infarction. The American Journal of Pathology 170:1, 33-42
CrossRef43
Philippe Giral, Jean-François Kahn, Jean-Michel André, Valérie Carreau, Caroline Dourmap, Eric Bruckert, M. John Chapman. (2007) Carotid atherosclerosis is not related to past tuberculosis in hypercholesterolemic patients. Atherosclerosis 190:1, 150-155
CrossRef44
Murat V Kalayoglu, Joan W Miller. (2007) Infection, inflammation and age-related macular degeneration. Clinical & Experimental Ophthalmology 35:1, 3-4
CrossRef45
E. J. C. Goldstein, R. C. Owens, T. D. Nolin. (2006) Antimicrobial-Associated QT Interval Prolongation: Pointes of Interest. Clinical Infectious Diseases 43:12, 1603-1611
CrossRef46
John A. Farmer. 2006. Inflammatory Mediators and C-Reactive Protein. , 441-462.
CrossRef47
Robert N. Foley. (2006) Infections and Cardiovascular Disease in Patients with Chronic Kidney Disease. Advances in Chronic Kidney Disease 13:3, 205-208
CrossRef48
Sven Poppert, Katja Schlaupitz, Reinhard Marre, Rainer Voisard, Wolfgang Roessler, Dorothea Weckermann, Karl Weingärtner, Andreas Essig. (2006) Chlamydia pneumoniae in an ex vivo human artery culture model. Atherosclerosis 187:1, 50-56
CrossRef49
Firas F. Mussa, Hong Chai, Xinwen Wang, Qizhi Yao, Alan B. Lumsden, Changyi Chen. (2006) Chlamydia pneumoniae and vascular disease: An update. Journal of Vascular Surgery 43:6, 1301-1307
CrossRef50
Mark J. Donaldson, Jose S. Pulido. (2006) Treatment of nonexudative (dry) age-related macular degeneration. Current Opinion in Ophthalmology 17:3, 267-274
CrossRef51
David M Rothstein, Christo Shalish, Christopher K Murphy, Andrew Sternlicht, Lee Ann Campbell. (2006) Development potential of rifalazil and other benzoxazinorifamycins. Expert Opinion on Investigational Drugs 15:6, 603-623
CrossRef52
Alessandro Sionis. (2006) Estrategia de multidetección de Chlamydia pneumoniae en pacientes con enfermedad arterial periférica: el problema de evaluar la relación entre la infección y la enfermedad. Medicina Clínica 126:19, 740-741
CrossRef53
C??cile Courivaud, Christophe Ferrand, Marina Deschamps, Pierre Tiberghien, Jean-Marc Chalopin, Anne Duperrier, Philippe Saas, Didier Ducloux. (2006) No Evidence of Association between NOD2/CARD15 Gene Polymorphism and Atherosclerotic Events after Renal Transplantation. Transplantation 81:8, 1212-1215
CrossRef54
Park-Wyllie, Laura Y., Juurlink, David N., Kopp, Alexander, Shah, Baiju R., Stukel, Therese A., Stumpo, Carmine, Dresser, Linda, Low, Donald E., Mamdani, Muhammad M., . (2006) Outpatient Gatifloxacin Therapy and Dysglycemia in Older Adults. New England Journal of Medicine 354:13, 1352-1361
Full Text55
Cecilia Cuffini, Luis Alberto Guzmán, Néstor Villegas, Carlos Eduardo Alonso, Leandro Martínez-Riera, Marcelo Rodríguez-Fermepín, Andrea Carolina Entrocassi, María Pilar Adamo, Mauro Pedranti, Marta Zapata. (2006) Isolation of Chlamydophila pneumoniae from atheromas of the carotid artery and their antibiotics susceptibility profile. Enfermedades Infecciosas y Microbiología Clínica 24:2, 81-85
CrossRef56
E Gurfinkel, V Lernoud. (2006) The role of infection and immunity in atherosclerosis. Expert Review of Cardiovascular Therapy 4:1, 131-137
CrossRef57
Alfredo Bardají, Joaquín Alonso, Xavier García-Moll, Héctor Bueno. (2006) Actualización en cardiopatía isquémica 2005. Revista Española de Cardiología 59, 3-19
CrossRef58
W HOWARD, W FRISHMAN. (2006) Intensive Lipid Lowering With Atorvastatin in Patients With Stable Coronary DiseaseLaRosa JC, for the Treating to New Targets (TNT) Investigators (State Univ of New York, Brooklyn; et al) N Engl J Med 352:1425–1435, 2005§. Yearbook of Medicine 2006, 480-482
CrossRef59
. (2005) Antibiotica geen oplossing voor coronairlijden. Huisarts en Wetenschap 48:12, 101-101
CrossRef60
R. Frothingham. (2005) Glucose Homeostasis Abnormalities Associated with Use of Gatifloxacin. Clinical Infectious Diseases 41:9, 1269-1276
CrossRef61
Jean A. Wiedeman, Ravi Kaul, Luke S. Heuer, Nao N. Thao, Kent E. Pinkerton, Wanda M. Wenman. (2005) Tobacco smoke induces a persistent, but recoverable state in Chlamydia pneumoniae infection of human endothelial cells. Microbial Pathogenesis 39:5-6, 197-204
CrossRef62
Thomas Dietrich, Raul I. Garcia. (2005) Associations Between Periodontal Disease and Systemic Disease: Evaluating the Strength of the Evidence. Journal of Periodontology 76:11-s, 2175-2184
CrossRef63
Antonio M. Gotto. (2005) Evolving Concepts of Dyslipidemia, Atherosclerosis, and Cardiovascular Disease. Journal of the American College of Cardiology 46:7, 1219-1224
CrossRef64
Laurence Senn, Margaret R Hammerschlag, Gilbert Greub. (2005) Therapeutic approaches to Chlamydia infections. Expert Opinion on Pharmacotherapy 6:13, 2281-2290
CrossRef65
Newton G. Osborne. (2005) Recurrent Acute Coronary Syndrome in Women: Is There a Future for Antibiotic Prophylaxis?. Journal of Gynecologic Surgery 21:3, 137-139
CrossRef66
Kazunori Shimada, Hiroyuki Daida, Wei Ma-Krupa, Jörg J Goronzy, Cornelia M Weyand. (2005) Lipopolysaccharide, CD14 and Toll-like receptors: an emerging link between innate immunity and atherosclerotic disease. Future Cardiology 1:5, 657-674
CrossRef67
Robert P. Giugliano, Eugene Braunwald. (2005) The Year in Non
ST-Segment Elevation Acute Coronary Syndromes. Journal of the American College of Cardiology 46:5, 906-919
CrossRef68
T. Vainas, F.R.M. Stassen, G.W.H. Schurink, J.H.M. Tordoir, R.J.Th.J. Welten, L.H.J.M. van den Akker, H.A.J.M. Kurvers, C.A. Bruggeman, P.J.E.H.M. Kitslaar. (2005) Reply to: Effect of Macrolides on Peripheral Arterial Disease Depends on Patient Selection and Adequate Treatment. P.A. Krayenbuehl, P. Wiesli, T. Meier, G. Schulthess. European Journal of Vascular and Endovascular Surgery 30:3, 337
CrossRef69
(2005) Chlamydia pneumoniae and Acute Coronary Syndrome. New England Journal of Medicine 353:5, 525-528
Full Text70
Anderson, Jeffrey L., . (2005) Infection, Antibiotics, and Atherothrombosis — End of the Road or New Beginnings?. New England Journal of Medicine 352:16, 1706-1709
Full Text71
Hansson, Göran K., . (2005) Inflammation, Atherosclerosis, and Coronary Artery Disease. New England Journal of Medicine 352:16, 1685-1695
Full Text72
Grayston, J. Thomas, Kronmal, Richard A., Jackson, Lisa A., Parisi, Alfred F., Muhlestein, Joseph B., Cohen, Jerome D., Rogers, William J., Crouse, John R., Borrowdale, Sandra L., Schron, Eleanor, Knirsch, Charles, . (2005) Azithromycin for the Secondary Prevention of Coronary Events. New England Journal of Medicine 352:16, 1637-1645
Full Text
- Letters
