It wasn’t too long ago that I reviewed pulmonary infections for a morning report (see summary here). We reviewed some fun facts including:
– 10 % of HCAP have atypical infections indicating the use of Azithromycin.
– For outpatient CAP treatment, IDSA recommends Azithromycin (other option being doxy)
– For inpatient CAP treatment, IDSA recommends either a respiratory fluoroquinolone or ceftriaxone + Azithromycin. (1)
Seems like in any pneumonia circumstance, you can’t go wrong with Azithromycin…
Except for a 2012 NEJM study that reported a “small absolute increase in cardiovascular death” (2). That’s terrifying! Fortunately, the FDA warned all physicians of this dire outcome with their statement:
“Health care professionals should consider the risk of fatal heart rhythms with azithromycin when considering treatment options for patients who are already at risk for cardiovascular events. FDA notes that the potential risk of QT prolongation with azithromycin should be placed in appropriate context when choosing an antibacterial drug: Alternative drugs in the macrolide class, or non-macrolides such as the fluoroquinolones, also have the potential for QT prolongation or other significant side effects that should be considered when choosing an antibacterial drug.” (3)
But let’s get back to the 2012 NEJM study (2):
– A cohort study of medicaid patients.
– Of the prescriptions with documented indication, 62% of the azithro scripts were for infections of the ear, nose, throat or bronchitis! I would immediately question the necessity of these scripts to begin with.
– The “small” increase in CV death for azithro was: 47 deaths per million courses overall and 245 deaths per million for patients in the highest category of cardiovascular disease. That’s a risk of 0.005% and 0.0245%, or a NNH of 21,277 and 4,082 respectively. Seems…less scary.
But what about our patients with pneumonia (a disease where antibiotic administration is actually indicated)?
Per a 2014, JAMA article (4)…
– Cohort study of patients >65 years old treated for pneumonia.
– 90 day mortality was 17.4% (95% CI, 17.0%-17.9%) for Azithro versus 22.3% (95% CI, 21.8%-22.7%) for nonusers (P<0.001).
– Cardiovascular events: MI occurred in 5.1% (95% CI, 4.8%-5.3%) in Azithro versus 4.4% (95% CI, 4.2%-4.6%) for nonusers (P<0.001)
– There was no difference in arrhythmias, incidence of heart failure, or over-all cardiac events. Keep in mind, this is in an older population, hence at higher risk for bad cardiovascular outcome.
Though it’s unclear why some patients received azithromycin versus another appropriate antibiotic, this study concludes that in older patients with pneumonia azithromycin lowers all cause mortality, despite increasing the rate of MI! In their discussion section, they reference numerous papers that report improved mortality in pneumonia treated with B-lactam plus azithromycin versus B-lactams alone (5 A-G).
See also a Swiss study that showed decreased readmissions and a trend (P=0.07) for reaching clinical stability in 7 days with a B-lactam AND Azithro versus a B-lactam alone. Patients with PSI score IV and those with atypical pathogens were statistically significantly less likely to reach clinical stability at 7 days. Mortality, ICU admission, and length of stay showed no difference.
So Azithro will kill our patients’ hearts…but not really…But at least it helps with pneumonia…
NEJM 2015 (7)
– Cluster-randomized, noninferiority trial of pneumonia patients admitted to the Non-ICU setting in the Netherlands treated with a B-lacatm, a B-lactam AND azithro, versus a fluoroquinolone.
– A median age of 70
– Atypical pathogens in 2.1%, with legionella < 1% (If not already, antibiotics were appropriately switched once legionella was diagnosed)
– For 90 day mortality, B-lactam alone was non-inferior to B-lactam + azithro and non-inferior to a fluoroquinolone with no difference in major or minor complications.
– As intention-to-treat analysis can confound non-inferiority trials, a post study ad-hoc analysis with adherence to antibiotic assigned yielded no difference in 90 day mortality.
Conclusion
BLACK BOX WARNING – Azithro will kill your patients…or maybe not
Regardless, it should be given in all patients with pneumonia…or maybe not
Maybe it hurts to give it…maybe it hurts not to give it. I’m sure the best strategy is to share these papers with each and every patient and engage in some joint decision making…or just do what your attending tells you to do.
By Andrew Grock
References
(1)Lionel A. Mandell,et al. Infectious Diseases Society of America/American Thoracic Society Consensus Guidelines on the Management of Community-Acquired Pneumonia in Adults
(4) Garin N, et al. β-Lactam monotherapy vs β-lactam-macrolide combination treatment in moderately severe community-acquired pneumonia: a randomized noninferiority trial.JAMA Intern Med. 2014 Dec;174(12):1894-901. doi: 10.1001/jamainternmed.2014.4887.
(5) A. Gleason PP, Meehan TP, Fine JM, Galusha DH, Fine MJ. Associations between initial antimicrobial
therapy and medical outcomes for hospitalized elderly patients with pneumonia. Arch Intern Med. 1999;159(21):2562-2572.
B. Stahl JE, Barza M, DesJardin J, Martin R, Eckman MH. Effect of macrolides as part of initial empiric
therapy on length of stay in patients hospitalized with community-acquired pneumonia. Arch Intern
Med. 1999;159(21):2576-2580.
C. Houck PM, MacLehose RF, Niederman MS,Lowery JK. Empiric antibiotic therapy and mortality
among Medicare pneumonia inpatients in 10 western states: 1993, 1995, and 1997. Chest. 2001;
119(5):1420-1426.
  D. Battleman DS, Callahan M, Thaler HT. 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. Arch Intern Med. 2002;162(6):682-688.
E. MartÃnez JA, Horcajada JP, AlmelaM, 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. Clin Infect Dis. 2003;36(4):389-395.
F. Waterer GW, Somes GW,Wunderink RG. Monotherapymay be suboptimal for severe
bacteremic pneumococcal pneumonia. Arch Intern Med. 2001;161(15):1837-1842.
G. RodrÃguez A, Mendia A, Sirvent JM, et al; CAPUCI Study Group. Combination antibiotic
therapy improves survival in patients with community-acquired pneumonia and shock. Crit
Care Med. 2007;35(6):1493-1498.
andygrock
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3 Comments
Jay Khadpe MD · April 21, 2015 at 3:55 am
When you’re an attending in 3 months, what will you do? Why not just go with the respiratory quinolone if concerned about the association of cv events with azithro?
Ian deSouza · April 21, 2015 at 12:41 pm
After such a nice blog post, you end with, “Do what your attending tells you to do”???? Attendings may benefit from education about this issue and shared decision-making with the knowledgable resident too.
Azithromycin is considered by many ID MDs to be too broad of an antibiotic for pneumonia and is contributing significantly to resistance. For outpatient management, amoxicillin will probably suffice, and doxycycline is a recommended alternative (which is what I have been using). For inpatients, I think we have to assume that IF the patient is to have an adverse effect from an antibiotic, then he/she is in a hospital with staff than can intervene if need be.
These “black box warnings” should be kept in mind but also kept in perspective.
andygrock · April 21, 2015 at 1:28 pm
Thanks for the great comments from you both.
To address your thoughtful comments
Khadpe – Agreed, you can definitely give a respiratory flouroquinolone instead of ceftriaxone/azithro as an inpatient or instead of azithro as an outpatient. My main problem here is more practical. I thought that moxifloxacin (for example) is expensive and not always covered by insurance. Also, I know our nurses can get ceftriaxone or azithro quickly from the pyxis, but I don’t think we have a respiratory fluoroquinolone in the pyxis.
2. Just a joke about doing whatever your attending says. Glad it got you feisty. Agreed that doxy should be fine for outpatient pna, but I haven’t seen evidence for or against using amox. I have read about its use in pediatric pneumonia, and that we shouldn’t be giving broader coverage.