Chlamydia pneumoniae and Acute Coronary Syndrome
http://www.100md.com
《新英格兰医药杂志》
To the Editor: Long-term antichlamydial antibiotic therapy did not alter the risk of cardiac events among patients with stable coronary disease, as reported by Grayston et al.,1 or after an acute coronary syndrome, as reported by Cannon et al.2 (April 21 issue). Unfortunately, neither of these studies used baseline serologic tests during patient selection. Consequently, only one third of patients had IgA antibody,1 and only 3.5 percent had chlamydial DNA in peripheral mononuclear blood cells.2 In the absence of persistent chlamydial infection among the majority of treated patients, there is little reason to expect a clinical benefit with antichlamydial treatment.
Serum IgA has been correlated with the presence of chlamydial DNA in tissue.3 Furthermore, we found that patients with an acute coronary syndrome who had a baseline IgA titer of 1:32 or higher were at significant risk for the development of myocardial necrosis associated with their index event.4 This finding highlights the biologic role and prognostic value of IgA, which may serve as a useful tool for patient selection in future clinical trials of antichlamydial treatment in coronary heart disease.
Brian Y.L. Wong, M.D.
Sudbury Regional Hospital
Sudbury, ON P3E 3Y9, Canada
Judy Gnarpe, Ph.D.
University of Alberta
Edmonton, AB T6G 2H7, Canada
References
Grayston JT, Kronmal RA, Jackson LA, et al. Azithromycin for the secondary prevention of coronary events. N Engl J Med 2005;352:1637-1645.
Cannon CP, Braunwald E, McCabe CH, et al. Antibiotic treatment of Chlamydia pneumoniae after acute coronary syndrome. N Engl J Med 2005;352:1646-1654.
Gnarpe J, Sparr A, Naas J, Lundback A. Serological analysis of specific IgA to Chlamydia pneumoniae: increased sensitivity of IgA antibody detection using prolonged incubation and high antigen concentration. APMIS 2000;108:357-362.
Wong BYL, Gnarpe J, Teo KK, et al. Does chronic Chlamydia pneumoniae infection increase the risk of myocardial injury? Insights from patients with non-ST-elevation acute coronary syndromes. Am Heart J 2002;144:987-994.
To the Editor: There is a substantial body of evidence that chlamydia contributes to the pathogenesis of atherosclerosis. The two large placebo-controlled clinical trials by Grayston et al. and Cannon et al., which involved treatment with either azithromycin or gatifloxacin, demonstrated that neither of these antibiotics modulates advanced atherosclerotic disease. Chlamydia pneumoniae is an intracellular microorganism with a complex life cycle in which the replicating agent can convert to a persistent, nonreplicating form (cryptic bodies) on exposure to a variety of stimuli, including antibiotics.1 The current mode of action of most antibiotics used as single-agent therapy will have minimal, if any, effect on the persistent, nonreplicating form of C. pneumoniae.2 The importance of combination antimicrobial therapy that inhibits various bacterial targets in human chlamydial-related disease has been demonstrated recently in a prospective trial involving patients with spondyloarthropathy (P<0.003 for the comparison between patients who had a response to therapy and those who did not have a response).3 Ideally, future trials should be based on an efficacious animal model at the same stage of pathogenesis as that of the proposed patient population and that is based on in vitro evidence of cryptic-body elimination as well as evidence of drug penetration into the key cellular elements of atheromatous plaques.
William M. Mitchell, M.D., Ph.D.
Charles W. Stratton, M.D.
Vanderbilt University School of Medicine
Nashville, TN 37232
bill.mitchell@vanderbilt.edu
References
Gieffers J, Rupp J, Gebert A, Solbach W, Klinger M. First-choice antibiotics at subinhibitory concentrations induce persistence of Chlamydia pneumoniae. Antimicrob Agents Chemother 2004;48:1402-1405.
Suchland RJ, Geisler WM, Stamm WE. Methodologies and cell lines used for antimicrobial susceptibility testing of Chlamydia spp. Antimicrob Agents Chemother 2003;47:636-642.
Carter JD, Valeriano J, Vasey FB. Doxycycline versus doxycycline and rifampin in undifferentiated spondyloarthropathy, with special reference to chlamydia-induced arthritis: a prospective, randomized 9-month comparison. J Rheumatol 2004;31:1973-1980.
To the Editor: Cannon and colleagues compare gatifloxacin with placebo for the secondary prevention of cardiovascular events. This trial provides a unique opportunity to evaluate the safety of gatifloxacin in a high-risk population. The authors discuss associations between gatifloxacin therapy and diarrhea, nausea, vomiting, new-onset diabetes, hyperglycemia, and hypoglycemia. Gatifloxacin has also been associated with torsades de pointes and other ventricular arrhythmias.1,2,3 Did the rates of torsades de pointes, ventricular arrhythmias, or sudden death differ between the two groups?
Gatifloxacin provided no significant benefit in terms of any of the predefined primary or secondary end points. However, in the gatifloxacin group there were trends toward increases in the rate of death from all causes (hazard ratio, 1.23; 95 percent confidence interval, 0.85 to 1.82) and of death from coronary artery disease (hazard ratio, 1.55; 95 percent confidence interval, 0.91 to 2.7) (Figure 3 of the article by Cannon et al.). How many deaths in each group were attributable to potential adverse drug effects, including hyperglycemia, hypoglycemia, torsades de pointes, ventricular arrhythmias, sudden death, hypersensitivity reactions, Clostridium difficile colitis, or seizures?3 The study drug was administered for 10 days each month. How many deaths in each group occurred on a day that the study drug was administered?
Richard Frothingham, M.D.
Veterans Affairs Medical Center
Durham, NC 27705
richard.frothingham@duke.edu
Dr. Frothingham reports having received honoraria from Bayer, Bristol-Myers Squibb, Ortho-McNeil, and Pfizer and having served as a consultant for Bayer, Ortho-McNeil, Otsuka, and Schering-Plough.
References
Frothingham R. Rates of torsades de pointes associated with ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, and moxifloxacin. Pharmacotherapy 2001;21:1468-1472.
Bertino JS Jr, Owens RC Jr, Carnes TD, Iannini PB. Gatifloxacin-associated corrected QT interval prolongation, torsades de pointes, and ventricular fibrillation in patients with known risk factors. Clin Infect Dis 2002;34:861-863.
Tequin (gatifloxacin). Princeton, N.J.: Bristol-Myers Squibb, November 2004 (package insert).
To the Editor: Cannon et al. and Grayston et al. appraised the effect of long-term antibiotic therapy for protection against cardiovascular disease and concluded that there was no benefit. However, these studies do not justly reflect the overall effect of the intervention. A major adverse event of prolonged antibiotic treatment — namely, the development of antibiotic resistance — has been neglected.
Assessment of efficacy entails the balance of benefit versus harm. Antibiotics are unique in that the major cost of their use is the development of resistance, which affects both the person treated and the environment. Thus, the intermittent administration of gatifloxacin for 18 months may be harmful. The claim that the use of azithromycin for the treatment of cardiovascular disease is prevalent, thereby justifying the (unassessed) risk of the trial, is poorly based.1
Pharmaceutical companies drive these studies, but it is clinicians' duty to impose a complete assessment of adverse events. These two trials are in line with previous meta-analyses2,3 that showed, with narrow confidence intervals, that there was no benefit associated with the use of antibiotics for cardiovascular protection. Together, these studies amount to 6270 patient-years of antibiotic exposure, with unknown ecologic impact. In the absence of such data, further trials are unjustified.
Mical Paul, M.D.
Abigail Fraser, M.P.H.
Leonard Leibovici, M.D.
Rabin Medical Center
Petah-Tikva 49100, Israel
pil1pel@zahav.net.il
References
Gimenez-Sanchez F, Butler JC, Jernigan DB, et al. Treating cardiovascular disease with antimicrobial agents: a survey of knowledge, attitudes, and practices among physicians in the United States. Clin Infect Dis 2001;33:171-176.
Wells BJ, Mainous AG III, Dickerson LM. Antibiotics for the secondary prevention of ischemic heart disease: a meta-analysis of randomized controlled trials. Arch Intern Med 2004;164:2156-2161.
Illoh KO, Illoh OC, Feseha HB, Hallenbeck JM. Antibiotics for vascular diseases: a meta-analysis of randomized controlled trials. Atherosclerosis 2005;179:403-412.
Drs. Grayston and Cannon reply: Drs. Mitchell and Stratton point out the potential difficulty in attempting to treat chronic chlamydial infections that may be due in part to transiently nonreplicating antibiotic-resistant forms of C. pneumoniae. Because our experience and the literature have shown the need for prolonged courses of antibiotics for the successful treatment of chronic chlamydial infections, such as trachoma, in both the ACES (Azithromycin for the Secondary Prevention of Coronary Events) and PROVE IT–TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22) trials we elected to use long courses (one to two years) of antibiotic therapy. The failure of these courses of antibiotics suggests that at this time there is no antibiotic intervention that can be practically administered and that is also effective in reducing the risk of secondary coronary events. The results of these studies do not preclude the possibility that a more effective antibiotic regimen will become available in the future.
Drs. Wong and Gnarpe suggest that baseline serologic tests for chlamydia should have been used to identify participants for our trials. Baseline serologic data were collected in both studies but were not used as admission criteria because we believed that there is not sufficient evidence that either the presence or the absence of C. pneumoniae antibody clearly identifies adults at increased risk of coronary events. In addition, these trials offered a unique opportunity to study serologic findings as an indicator of such susceptibility. We found in both trials that the presence of C. pneumoniae IgG antibody did not identify participants who had an increased susceptibility to events. The presence of C. pneumoniae IgA antibody was assessed in the ACES trial. A total of 1301 participants had IgA antibody, and 2620 did not. IgA antibody was not associated with the risk of the primary end point in either the azithromycin group or the placebo group. Persons with IgA antibody were not shown to be more susceptible to cardiac events than were those without the antibody.
Dr. Frothingham asks about reactions to gatifloxacin. Of the 119 deaths in the PROVE IT–TIMI 22 trial, 19 occurred before the administration of the antibiotic study drug, which began on day 15. Of the remaining deaths, 50 had cardiovascular causes, as classified by the clinical events committee; of these, sudden death occurred in 9 patients in the gatifloxacin group and in 11 in the placebo group. Nonfatal ventricular arrhythmias reported as serious adverse events occurred in 16 patients in each group. Torsades de pointes was not reported as a serious adverse event in either group. Hyperglycemia and hypoglycemia were more common in the gatifloxacin group than in the placebo group, as reported in the article, but no episodes were fatal. Colitis developed in one patient receiving gatifloxacin, in whom it was necessary to stop the study drug, and in none of the patients in the placebo group. (The case of colitis was not reported to be caused by C. difficile.) One patient in the gatifloxacin group and none of the patients in the placebo group had seizures that led to discontinuation of the study drug. Thus, despite monthly courses of gatifloxacin for an average of two years, there did not appear to be major adverse events attributable to the known side effects of the drug. We hope this information is helpful to physicians.
Dr. Paul and colleagues raise the issue of antibiotic resistance. Prolonged courses of antibiotics are currently indicated for a variety of conditions, including acne. This safety concern was considered in the design of both trials. If a benefit of prolonged antibiotic therapy in the prevention of cardiac events had been demonstrated, further research on the possible risks associated with this treatment would be needed to assess the balance of risks and benefits. In their letter, Dr. Paul and colleagues dismiss the importance of the ongoing practice of antibiotic treatment of coronary heart disease. The review committee of the National Heart, Lung, and Blood Institute that recommended funding of the ACES trial stated as one of the reasons for their recommendation that there was "current antibiotic treatment of coronary heart disease without evidence of its effectiveness."
Both trials were initiated and planned by the investigators. All data analysis, interpretation, and reporting were performed by the investigators, independent of influence from pharmaceutical companies.
We understood when we planned these antibiotic trials that additional information concerning the role of C. pneumoniae in atherosclerosis and the treatment of chronic atherosclerotic lesions would be desirable. We believed that the possibility of an additional effective treatment for coronary heart disease was of such importance to the public health that we undertook the trials with the information then available.
J. Thomas Grayston, M.D.
University of Washington
Seattle, WA 98195
for the ACES Investigators
Christopher P. Cannon, M.D.
Brigham and Women's Hospital
Boston, MA 02115
cpcannon@partners.org
Serum IgA has been correlated with the presence of chlamydial DNA in tissue.3 Furthermore, we found that patients with an acute coronary syndrome who had a baseline IgA titer of 1:32 or higher were at significant risk for the development of myocardial necrosis associated with their index event.4 This finding highlights the biologic role and prognostic value of IgA, which may serve as a useful tool for patient selection in future clinical trials of antichlamydial treatment in coronary heart disease.
Brian Y.L. Wong, M.D.
Sudbury Regional Hospital
Sudbury, ON P3E 3Y9, Canada
Judy Gnarpe, Ph.D.
University of Alberta
Edmonton, AB T6G 2H7, Canada
References
Grayston JT, Kronmal RA, Jackson LA, et al. Azithromycin for the secondary prevention of coronary events. N Engl J Med 2005;352:1637-1645.
Cannon CP, Braunwald E, McCabe CH, et al. Antibiotic treatment of Chlamydia pneumoniae after acute coronary syndrome. N Engl J Med 2005;352:1646-1654.
Gnarpe J, Sparr A, Naas J, Lundback A. Serological analysis of specific IgA to Chlamydia pneumoniae: increased sensitivity of IgA antibody detection using prolonged incubation and high antigen concentration. APMIS 2000;108:357-362.
Wong BYL, Gnarpe J, Teo KK, et al. Does chronic Chlamydia pneumoniae infection increase the risk of myocardial injury? Insights from patients with non-ST-elevation acute coronary syndromes. Am Heart J 2002;144:987-994.
To the Editor: There is a substantial body of evidence that chlamydia contributes to the pathogenesis of atherosclerosis. The two large placebo-controlled clinical trials by Grayston et al. and Cannon et al., which involved treatment with either azithromycin or gatifloxacin, demonstrated that neither of these antibiotics modulates advanced atherosclerotic disease. Chlamydia pneumoniae is an intracellular microorganism with a complex life cycle in which the replicating agent can convert to a persistent, nonreplicating form (cryptic bodies) on exposure to a variety of stimuli, including antibiotics.1 The current mode of action of most antibiotics used as single-agent therapy will have minimal, if any, effect on the persistent, nonreplicating form of C. pneumoniae.2 The importance of combination antimicrobial therapy that inhibits various bacterial targets in human chlamydial-related disease has been demonstrated recently in a prospective trial involving patients with spondyloarthropathy (P<0.003 for the comparison between patients who had a response to therapy and those who did not have a response).3 Ideally, future trials should be based on an efficacious animal model at the same stage of pathogenesis as that of the proposed patient population and that is based on in vitro evidence of cryptic-body elimination as well as evidence of drug penetration into the key cellular elements of atheromatous plaques.
William M. Mitchell, M.D., Ph.D.
Charles W. Stratton, M.D.
Vanderbilt University School of Medicine
Nashville, TN 37232
bill.mitchell@vanderbilt.edu
References
Gieffers J, Rupp J, Gebert A, Solbach W, Klinger M. First-choice antibiotics at subinhibitory concentrations induce persistence of Chlamydia pneumoniae. Antimicrob Agents Chemother 2004;48:1402-1405.
Suchland RJ, Geisler WM, Stamm WE. Methodologies and cell lines used for antimicrobial susceptibility testing of Chlamydia spp. Antimicrob Agents Chemother 2003;47:636-642.
Carter JD, Valeriano J, Vasey FB. Doxycycline versus doxycycline and rifampin in undifferentiated spondyloarthropathy, with special reference to chlamydia-induced arthritis: a prospective, randomized 9-month comparison. J Rheumatol 2004;31:1973-1980.
To the Editor: Cannon and colleagues compare gatifloxacin with placebo for the secondary prevention of cardiovascular events. This trial provides a unique opportunity to evaluate the safety of gatifloxacin in a high-risk population. The authors discuss associations between gatifloxacin therapy and diarrhea, nausea, vomiting, new-onset diabetes, hyperglycemia, and hypoglycemia. Gatifloxacin has also been associated with torsades de pointes and other ventricular arrhythmias.1,2,3 Did the rates of torsades de pointes, ventricular arrhythmias, or sudden death differ between the two groups?
Gatifloxacin provided no significant benefit in terms of any of the predefined primary or secondary end points. However, in the gatifloxacin group there were trends toward increases in the rate of death from all causes (hazard ratio, 1.23; 95 percent confidence interval, 0.85 to 1.82) and of death from coronary artery disease (hazard ratio, 1.55; 95 percent confidence interval, 0.91 to 2.7) (Figure 3 of the article by Cannon et al.). How many deaths in each group were attributable to potential adverse drug effects, including hyperglycemia, hypoglycemia, torsades de pointes, ventricular arrhythmias, sudden death, hypersensitivity reactions, Clostridium difficile colitis, or seizures?3 The study drug was administered for 10 days each month. How many deaths in each group occurred on a day that the study drug was administered?
Richard Frothingham, M.D.
Veterans Affairs Medical Center
Durham, NC 27705
richard.frothingham@duke.edu
Dr. Frothingham reports having received honoraria from Bayer, Bristol-Myers Squibb, Ortho-McNeil, and Pfizer and having served as a consultant for Bayer, Ortho-McNeil, Otsuka, and Schering-Plough.
References
Frothingham R. Rates of torsades de pointes associated with ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, and moxifloxacin. Pharmacotherapy 2001;21:1468-1472.
Bertino JS Jr, Owens RC Jr, Carnes TD, Iannini PB. Gatifloxacin-associated corrected QT interval prolongation, torsades de pointes, and ventricular fibrillation in patients with known risk factors. Clin Infect Dis 2002;34:861-863.
Tequin (gatifloxacin). Princeton, N.J.: Bristol-Myers Squibb, November 2004 (package insert).
To the Editor: Cannon et al. and Grayston et al. appraised the effect of long-term antibiotic therapy for protection against cardiovascular disease and concluded that there was no benefit. However, these studies do not justly reflect the overall effect of the intervention. A major adverse event of prolonged antibiotic treatment — namely, the development of antibiotic resistance — has been neglected.
Assessment of efficacy entails the balance of benefit versus harm. Antibiotics are unique in that the major cost of their use is the development of resistance, which affects both the person treated and the environment. Thus, the intermittent administration of gatifloxacin for 18 months may be harmful. The claim that the use of azithromycin for the treatment of cardiovascular disease is prevalent, thereby justifying the (unassessed) risk of the trial, is poorly based.1
Pharmaceutical companies drive these studies, but it is clinicians' duty to impose a complete assessment of adverse events. These two trials are in line with previous meta-analyses2,3 that showed, with narrow confidence intervals, that there was no benefit associated with the use of antibiotics for cardiovascular protection. Together, these studies amount to 6270 patient-years of antibiotic exposure, with unknown ecologic impact. In the absence of such data, further trials are unjustified.
Mical Paul, M.D.
Abigail Fraser, M.P.H.
Leonard Leibovici, M.D.
Rabin Medical Center
Petah-Tikva 49100, Israel
pil1pel@zahav.net.il
References
Gimenez-Sanchez F, Butler JC, Jernigan DB, et al. Treating cardiovascular disease with antimicrobial agents: a survey of knowledge, attitudes, and practices among physicians in the United States. Clin Infect Dis 2001;33:171-176.
Wells BJ, Mainous AG III, Dickerson LM. Antibiotics for the secondary prevention of ischemic heart disease: a meta-analysis of randomized controlled trials. Arch Intern Med 2004;164:2156-2161.
Illoh KO, Illoh OC, Feseha HB, Hallenbeck JM. Antibiotics for vascular diseases: a meta-analysis of randomized controlled trials. Atherosclerosis 2005;179:403-412.
Drs. Grayston and Cannon reply: Drs. Mitchell and Stratton point out the potential difficulty in attempting to treat chronic chlamydial infections that may be due in part to transiently nonreplicating antibiotic-resistant forms of C. pneumoniae. Because our experience and the literature have shown the need for prolonged courses of antibiotics for the successful treatment of chronic chlamydial infections, such as trachoma, in both the ACES (Azithromycin for the Secondary Prevention of Coronary Events) and PROVE IT–TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22) trials we elected to use long courses (one to two years) of antibiotic therapy. The failure of these courses of antibiotics suggests that at this time there is no antibiotic intervention that can be practically administered and that is also effective in reducing the risk of secondary coronary events. The results of these studies do not preclude the possibility that a more effective antibiotic regimen will become available in the future.
Drs. Wong and Gnarpe suggest that baseline serologic tests for chlamydia should have been used to identify participants for our trials. Baseline serologic data were collected in both studies but were not used as admission criteria because we believed that there is not sufficient evidence that either the presence or the absence of C. pneumoniae antibody clearly identifies adults at increased risk of coronary events. In addition, these trials offered a unique opportunity to study serologic findings as an indicator of such susceptibility. We found in both trials that the presence of C. pneumoniae IgG antibody did not identify participants who had an increased susceptibility to events. The presence of C. pneumoniae IgA antibody was assessed in the ACES trial. A total of 1301 participants had IgA antibody, and 2620 did not. IgA antibody was not associated with the risk of the primary end point in either the azithromycin group or the placebo group. Persons with IgA antibody were not shown to be more susceptible to cardiac events than were those without the antibody.
Dr. Frothingham asks about reactions to gatifloxacin. Of the 119 deaths in the PROVE IT–TIMI 22 trial, 19 occurred before the administration of the antibiotic study drug, which began on day 15. Of the remaining deaths, 50 had cardiovascular causes, as classified by the clinical events committee; of these, sudden death occurred in 9 patients in the gatifloxacin group and in 11 in the placebo group. Nonfatal ventricular arrhythmias reported as serious adverse events occurred in 16 patients in each group. Torsades de pointes was not reported as a serious adverse event in either group. Hyperglycemia and hypoglycemia were more common in the gatifloxacin group than in the placebo group, as reported in the article, but no episodes were fatal. Colitis developed in one patient receiving gatifloxacin, in whom it was necessary to stop the study drug, and in none of the patients in the placebo group. (The case of colitis was not reported to be caused by C. difficile.) One patient in the gatifloxacin group and none of the patients in the placebo group had seizures that led to discontinuation of the study drug. Thus, despite monthly courses of gatifloxacin for an average of two years, there did not appear to be major adverse events attributable to the known side effects of the drug. We hope this information is helpful to physicians.
Dr. Paul and colleagues raise the issue of antibiotic resistance. Prolonged courses of antibiotics are currently indicated for a variety of conditions, including acne. This safety concern was considered in the design of both trials. If a benefit of prolonged antibiotic therapy in the prevention of cardiac events had been demonstrated, further research on the possible risks associated with this treatment would be needed to assess the balance of risks and benefits. In their letter, Dr. Paul and colleagues dismiss the importance of the ongoing practice of antibiotic treatment of coronary heart disease. The review committee of the National Heart, Lung, and Blood Institute that recommended funding of the ACES trial stated as one of the reasons for their recommendation that there was "current antibiotic treatment of coronary heart disease without evidence of its effectiveness."
Both trials were initiated and planned by the investigators. All data analysis, interpretation, and reporting were performed by the investigators, independent of influence from pharmaceutical companies.
We understood when we planned these antibiotic trials that additional information concerning the role of C. pneumoniae in atherosclerosis and the treatment of chronic atherosclerotic lesions would be desirable. We believed that the possibility of an additional effective treatment for coronary heart disease was of such importance to the public health that we undertook the trials with the information then available.
J. Thomas Grayston, M.D.
University of Washington
Seattle, WA 98195
for the ACES Investigators
Christopher P. Cannon, M.D.
Brigham and Women's Hospital
Boston, MA 02115
cpcannon@partners.org