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Macrolide Therapy for
Pneumonia: Balancing Benefits
with Cardiovascular Risks
Eric Mortensen, MD, MSc, FACP
Faculty Disclosure
• I have no relevant conflicts of interest nor
will discuss “off label” use of any
medications
Community-Acquired
Pneumonia (CAP)
• Leading infectious cause of death
• Since 1950 mortality has been stable or
increasing
• Increased incidence with aging of the
population
CAP Clinical Practice Guidelines
•
•
•
•
•
•
•
ATS- 1993 and 2001
IDSA- 1998, 2000, and 2003
BTS- 1993 and 2001
CIDS/CTS- 1993 and 2000
CDC- 2000
ERS- 2005 and 2011
IDSA/ATS- 2007
Mandell et al. ,Clin Infect Dis, 2007. 44 Suppl 2: p. S27
Woodhead et al. Clin Micro Infect 2011. 17 Suppl. 6, 1–24
IDSA/ATS Outpatient Antibiotic
Recommendations
• No risk factors for drug resistant S.
pneumoniae (DRSP)
• Macrolide or doxycycline
• Has risk factors for DRSP or significant
comorbid conditions
• Anti-pneumococcal fluoroquinolone
• -lactam + macrolide or doxycycline
IDSA/ATS Inpatient Antibiotic
Recommendations
• Wards
 -lactam + macrolide or doxycycline
– Anti-pneumococcal fluoroquinolone alone
• ICU
 -lactam + azithromycin or fluoroquinolone
Beneficial Effects of Macrolides on the Inflamed Airway
Kanoh S , and Rubin B K Clin. Microbiol. Rev. 2010;23:590-615
Macrolides for Pneumonia
• Erythromycin
• Clarithromycin
• Azithromycin
Factors Associated With Mortality And Lengthy Of Stay In Elderly
Patients With CAP- Azithromycin vs. Clarithromycin
Sánchez F et al. Clin Infect Dis. 2003;36:1239-1245
Macrolide versus non-macrolide therapy and mortality in critically ill
patients with community-acquired pneumonia: primary analysis (n=27)
Sligl, W, et al. Critical Care Medicine. 42(2):420-432
Ray WA, et al. NEJM. May 17 2012; 366(20):1881-1890
Cumulative Incidence of Cardiovascular Death and Death from Any
Cause for Patients Who Took Azithromycin vs Amoxicillin
Ray WA et al. N Engl J Med 2012;366:1881-1890.
Cardiovascular Death and Death from Any Cause among Patients
Who Took Azithromycin vs. no Antibiotics
Ray WA et al. N Engl J Med 2012;366:1881-1890.
Svanström H et al. N Engl J Med 2013;368:1704-1712
Risk of Death from Cardiovascular Causes with Azithromycin Use as
Compared with No Antibiotic Use or Use of Penicillin V
Svanström H et al. N Engl J Med 2013;368:1704-1712
Subgroup Analyses of the Risk of Death from Cardiovascular
Causes with Current Use of Azithromycin as Compared with
Penicillin V
Svanström H et al. N Engl J Med 2013;368:1704-1712
EM Mortensen and coauthors
Association of Azithromycin With Mortality
and Cardiovascular Events Among Older
Patients Hospitalized With Pneumonia
Available at jama.com and
on The JAMA Network Reader at
mobile.jamanetwork.com
jamanetwork.com
Aim: To examine the association of
azithromycin use with all-cause mortality
and cardiovascular events for older patients
hospitalized with pneumonia
Mortensen et al. JAMA 2014
Inclusion Criteria
• Hospitalized with pneumonia in VA health
care system between FY 2002 and 2012
• > 65 years old
• >3 outpatient visits in year prior & received
outpatient medications
• Received guideline-concordant antibiotic
therapy and first dose given within 48 hours
of admission
Guideline-Concordant Antibiotic
Regimes
• Wards
– Beta-lactam + azithromycin
– Antipneumococcal fluoroquinolone alone
• ICU
– Beta-lactam + azithromycin
– Beta-lactam + fluoroquinolone
Mandell LA, et al. Clin Infect Dis. Mar 1 2007;44 Suppl 2:S27-72
Primary Outcomes
• Mortality within 90-days
• Cardiovascular events within 90-days
– MI
– Heart failure
– Arrhythmia
– Any
Statistical Analyses
• Propensity matching with score created
using 59 variables including:
–
–
–
–
Demographics (age, race, marital status)
Comorbid conditions
Severity of illness (ICU, vasopressors)
Outpatient medications (statins, anti-diabetic)
• Instrumental variable analysis
– Chosen IV was proportion of patients receiving
azithromycin in each hospital
Results
• Overall 73,690 patients from 118 hospitals
meet inclusion criteria
• Propensity-matched group composed of
63,726 patients
Variable
Age, mean (SD)
Men
Married
ICU admission
Mechanical ventilation
Tobacco use
Alcohol abuse
Myocardial infarction
Heart failure
COPD
Prior antibiotic therapy
Azithromycin
N=31,863
77.8 (7.4)
98.2%
52.5%
15.6%
5.2%
39.7%
4.5%
7.1%
25.7%
51.8%
31.3%
No Azithromycin
N=31,863
77.8 (7.4)
98.2%
52.4%
15.5%
5.3%
39.7%
4.5%
7.0%
25.6%
51.7%
31.1%
After matching no significant differences (all p >0.3)
Survival Curves by Azithromycin Use vs Nonuse
Time to First Cardiac Event by Azithromycin Use vs
Nonuse
Outcomes after Propensity
Matching
Outcome
Odds Ratio
95% CI
90-day mortality
MI
Arrhythmia
Heart failure
Any CV event
0.73
1.17
0.99
1.01
1.01
0.70-0.76
1.08-1.25
0.95-1.02
0.97-1.04
0.98-1.05
Instrumental Variable Analysis
Average
Marginal Effect
Outcome
of Azithromycin
Mortality
-0.08
Any CV Event
-0.004
Heart Failure
-0.04
MI
0.03
Arrhythmia
0.01
Azithromycin users had
• 8% lower probability of mortality
• 4% lower probability of HF
• 3% higher probability of MI
Bootstrapped
95% CI
-0.10 to -0.07
-0.02 to 0.02
-0.06 to -0.02
0.02 to 0.04
-0.01 to 0.03
Secondary Analyses
• No prior outpatient antibiotics
– 90-day mortality OR 0.74 (0.71-0.78)
– Any CV event OR 1.02 (0.97-1.06)
• Prior cardiac disease
– 90-day mortality OR 0.72 (0.67-0.77)
– Any CV event OR 1.04 (0.97-1.11)
• Invasive mechanical ventilation
– 90- day mortality OR 0.81 (0.70-0.93)
– Any CV event OR 1.24 (1.08-1.43)
ConclusionsAzithromycin and CAP
• Azithromycin use associated with lower
mortality but higher rate of MI
– NNT to prevent 1 death- 21
– NNH to cause 1 MI- 144
– Net benefit: 7 deaths averted for each non-fatal
MI
Summary
• Macrolides are part of guidelineconcordant pneumonia therapy
• Azithromycin is associated with some
increased cardiac risks, but…
• For pneumonia, benefits of
azithromycin outweigh risks
Questions?
Eric.Mortensen@UTSouthwestern.edu