Association of azithromycin with mortality and cardiovascular events among older patients hospitalized with pneumonia.

IMPORTANCE Although clinical practice guidelines recommend combination therapy with macrolides, including azithromycin, as first-line therapy for patients hospitalized with pneumonia, recent research suggests that azithromycin may be associated with increased cardiovascular events. OBJECTIVE To examine the association of azithromycin use with all-cause mortality and cardiovascular events for patients hospitalized with pneumonia. DESIGN Retrospective cohort study comparing older patients hospitalized with pneumonia from fiscal years 2002 through 2012 prescribed azithromycin therapy and patients receiving other guideline-concordant antibiotic therapy. SETTING This study was conducted using national Department of Veterans Affairs administrative data of patients hospitalized at any Veterans Administration acute care hospital. PARTICIPANTS Patients were included if they were aged 65 years or older, were hospitalized with pneumonia, and received antibiotic therapy concordant with national clinical practice guidelines. MAIN OUTCOMES AND MEASURES Outcomes included 30- and 90-day all-cause mortality and 90-day cardiac arrhythmias, heart failure, myocardial infarction, and any cardiac event. Propensity score matching was used to control for the possible effects of known confounders with conditional logistic regression. RESULTS Of 73,690 patients from 118 hospitals identified, propensity-matched groups were composed of 31,863 patients exposed to azithromycin and 31,863 matched patients who were not exposed. There were no significant differences in potential confounders between groups after matching. Ninety-day mortality was significantly lower in those who received azithromycin (exposed, 17.4%, vs unexposed, 22.3%; odds ratio [OR], 0.73; 95% CI, 0.70-0.76). However, we found significantly increased odds of myocardial infarction (5.1% vs 4.4%; OR, 1.17; 95% CI, 1.08-1.25) but not any cardiac event (43.0% vs 42.7%; OR, 1.01; 95% CI, 0.98-1.05), cardiac arrhythmias (25.8% vs 26.0%; OR, 0.99; 95% CI, 0.95-1.02), or heart failure (26.3% vs 26.2%; OR, 1.01; 95% CI, 0.97-1.04). CONCLUSIONS AND RELEVANCE Among older patients hospitalized with pneumonia, treatment that included azithromycin compared with other antibiotics was associated with a lower risk of 90-day mortality and a smaller increased risk of myocardial infarction. These findings are consistent with a net benefit associated with azithromycin use.

[1]  Melonie P. Heron Deaths: Leading Causes for 2012. , 2015, National vital statistics reports : from the Centers for Disease Control and Prevention, National Center for Health Statistics, National Vital Statistics System.

[2]  Jesse Loar Use of Azithromycin and Death from Cardiovascular Causes , 2013 .

[3]  A. Anzueto,et al.  Comparison of two guideline-concordant antimicrobial combinations in elderly patients hospitalized with severe community-acquired pneumonia* , 2012, Critical care medicine.

[4]  T. Marrie,et al.  Macrolide-based regimens and mortality in hospitalized patients with community-acquired pneumonia: a systematic review and meta-analysis. , 2012, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[5]  H. Imaoka,et al.  Azithromycin and the risk of cardiovascular death. , 2012, The New England journal of medicine.

[6]  A. Anzueto,et al.  Incidence of cardiovascular events after hospital admission for pneumonia. , 2011, The American journal of medicine.

[7]  J. Kmenta Mostly Harmless Econometrics: An Empiricist's Companion , 2010 .

[8]  R. Wunderink,et al.  Impact of macrolide therapy on mortality for patients with severe sepsis due to pneumonia , 2009, European Respiratory Journal.

[9]  J. Ramirez,et al.  Acute myocardial infarction in hospitalized patients with community-acquired pneumonia. , 2008, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[10]  Paul J Rathouz,et al.  Two-stage residual inclusion estimation: addressing endogeneity in health econometric modeling. , 2008, Journal of health economics.

[11]  C. Hsia,et al.  Azithromycin‐Induced Torsade De Pointes , 2007, Pacing and clinical electrophysiology : PACE.

[12]  L. Cosler,et al.  Comparison of β-Lactam and Macrolide Combination Therapy versus Fluoroquinolone Monotherapy in Hospitalized Veterans Affairs Patients with Community-Acquired Pneumonia , 2007, Antimicrobial Agents and Chemotherapy.

[13]  D. Musher,et al.  The association between pneumococcal pneumonia and acute cardiac events. , 2007, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[14]  J. Rello,et al.  Combination antibiotic therapy improves survival in patients with community-acquired pneumonia and shock* , 2007, Critical care medicine.

[15]  J. Bartlett,et al.  Infectious Diseases Society of America/American Thoracic Society Consensus Guidelines on the Management of Community-Acquired Pneumonia in Adults , 2007, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[16]  A. Ma,et al.  Antibiotics for bacteremic pneumonia: Improved outcomes with macrolides but not fluoroquinolones. , 2007, Chest.

[17]  Melonie P. Heron,et al.  Deaths: leading causes for 2003 [U.S.A.] , 2007 .

[18]  L. Cosler,et al.  Comparison of beta-lactam and macrolide combination therapy versus fluoroquinolone monotherapy in hospitalized Veterans Affairs patients with community-acquired pneumonia. , 2007, Antimicrobial agents and chemotherapy.

[19]  T. Nolin,et al.  Antimicrobial-associated QT interval prolongation: pointes of interest. , 2006, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[20]  C. Frei,et al.  Impact of guideline-concordant empiric antibiotic therapy in community-acquired pneumonia. , 2006, The American journal of medicine.

[21]  C. Maynard,et al.  Accuracy and completeness of mortality data in the Department of Veterans Affairs , 2006, Population health metrics.

[22]  A. Anzueto,et al.  The impact of empiric antimicrobial therapy with a β-lactam and fluoroquinolone on mortality for patients hospitalized with severe pneumonia , 2005, Critical care.

[23]  A. Anzueto,et al.  Effects of guideline-concordant antimicrobial therapy on mortality among patients with community-acquired pneumonia. , 2004, The American journal of medicine.

[24]  J. Tamaoki,et al.  Clinical implications of the immunomodulatory effects of macrolides. , 2004, The American journal of medicine.

[25]  Y. Oki,et al.  A case of QT-interval prolongation precipitated by azithromycin. , 2003, The New Zealand medical journal.

[26]  Christopher M O'Connor,et al.  Azithromycin for the secondary prevention of coronary heart disease events: the WIZARD study: a randomized controlled trial. , 2003, JAMA.

[27]  H. Mukae,et al.  Long-term efficacy and safety of clarithromycin treatment in patients with diffuse panbronchiolitis. , 2003, Respiratory medicine.

[28]  Á. Soriano,et al.  Addition of a macrolide to a beta-lactam-based empirical antibiotic regimen is associated with lower in-hospital mortality for patients with bacteremic pneumococcal pneumonia. , 2003, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[29]  B. Sianesi,et al.  PSMATCH2: Stata module to perform full Mahalanobis and propensity score matching, common support graphing, and covariate imbalance testing , 2003 .

[30]  M. Parnham,et al.  Azithromycin modulates neutrophil function and circulating inflammatory mediators in healthy human subjects. , 2002, European journal of pharmacology.

[31]  M. Fine,et al.  Causes of death for patients with community-acquired pneumonia: results from the Pneumonia Patient Outcomes Research Team cohort study. , 2002, Archives of internal medicine.

[32]  D. Battleman,et al.  Rapid antibiotic delivery and appropriate antibiotic selection reduce length of hospital stay of patients with community-acquired pneumonia: link between quality of care and resource utilization. , 2002, Archives of internal medicine.

[33]  M. Parnham,et al.  Anti-inflammatory effects of macrolide antibiotics. , 2001, European journal of pharmacology.

[34]  R. Wunderink,et al.  Monotherapy may be suboptimal for severe bacteremic pneumococcal pneumonia. , 2001, Archives of internal medicine.

[35]  M. Niederman,et al.  Empiric antibiotic therapy and mortality among medicare pneumonia inpatients in 10 western states : 1993, 1995, and 1997. , 2001, Chest.

[36]  G. Hutchins,et al.  Problems with proper completion and accuracy of the cause-of-death statement. , 2001, Archives of internal medicine.

[37]  F. D’Acquisto,et al.  Anti-inflammatory activity of macrolide antibiotics. , 2000, The Journal of pharmacology and experimental therapeutics.

[38]  J E Stahl,et al.  Effect of macrolides as part of initial empiric therapy on length of stay in patients hospitalized with community-acquired pneumonia. , 1999, Archives of internal medicine.

[39]  M. Fine,et al.  Associations between initial antimicrobial therapy and medical outcomes for hospitalized elderly patients with pneumonia. , 1999, Archives of internal medicine.

[40]  B. Horne,et al.  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. , 1999, Circulation.

[41]  S. Kudoh,et al.  Improvement of survival in patients with diffuse panbronchiolitis treated with low-dose erythromycin. , 1998, American journal of respiratory and critical care medicine.

[42]  L. Kazis,et al.  Health-related quality of life in patients served by the Department of Veterans Affairs: results from the Veterans Health Study. , 1998, Archives of internal medicine.

[43]  M. Labro Anti-inflammatory activity of macrolides: a new therapeutic potential? , 1998, The Journal of antimicrobial chemotherapy.

[44]  M. Nakazato,et al.  Elevated concentrations of defensins in bronchoalveolar lavage fluid in diffuse panbronchiolitis. , 1998, The European respiratory journal.

[45]  M. Fine,et al.  Quality of care, process, and outcomes in elderly patients with pneumonia. , 1997, JAMA.

[46]  R. Deyo,et al.  Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. , 1992, Journal of clinical epidemiology.

[47]  T. Izumi,et al.  [Long-term therapeutic effects of erythromycin and newquinolone antibacterial agents on diffuse panbronchiolitis]. , 1990, Nihon Kyobu Shikkan Gakkai zasshi.