The

n e w e ng l a n d j o u r na l

To the Editor: Wenzel et al. review the use of

macrolide therapy for the prevention of COPD exacerbations. However, we have some concerns
about the extrapolation of their conclusions
worldwide. Different epidemiologic characteristics, rates of antibiotic resistance, and mechanisms of resistance among respiratory pathogens
could be encountered in different countries.
The prevalence of macrolide-resistant Streptococcus pneumoniae, a major type of bacteria isolated in patients admitted for COPD exacerbation, is close to 96% in some Asian countries.1
Moreover, there are two common mechanisms
of macrolide resistance in S. pneumoniae. The first
mechanism involves the site where macrolides
bind to the ribosome; this mechanism accounts
for more than 90% of the macrolide-resistant
isolate strains in Europe and confers high resistance (minimum inhibitory concentration, 64
g per milliliter).2 The second mechanism is
caused by an efflux pump; this mechanism accounts for more than 65% of the macrolide-resistant isolate strains in the United States3 and
confers a low level of macrolide resistance
(minimum inhibitory concentration, 4 g per
milliliter). The study conducted by Albert et al.4
was performed in the United States.
Before the use of azithromycin can be recommended worldwide, further studies should be
performed in different geographic areas.
Carolina Garcia-Vidal, M.D., Ph.D.
Diego Viasus, M.D., Ph.D.
Jordi Carratal, M.D., Ph.D.

of

m e dic i n e

To the Editor: In their review of long-term azith

romycin use for prevention of COPD exacerbations, Wenzel and coauthors acknowledge the
risk of the development of infection with macrolide-resistant nontuberculous mycobacteria, and
they recommend screening for mycobacteria before the initiation of azithromycin therapy and
not administering this prophylaxis to patients
with positive sputum cultures. The relationship
between macrolides and nontuberculous mycobacteria may be more complex than described,
however. In addition to the specific risk of macrolide resistance,1 retrospective studies involving
patients with cystic fibrosis suggest that azithromycin may increase the risk of the development
of infections with nontuberculous mycobacteria,2,3 and widespread use of long-term azithromycin may in part explain the alarming increase
in the incidence of infections with nontuberculous mycobacteria observed in patients with
cystic fibrosis. Experimental evidence suggests a
paradoxical effect of azithromycin on nontuberculous mycobacteria, with bactericidal effects
offset by reduced mycobacterial killing through
inhibition of macrophage autophagy3 a more
complex picture than that depicted in Figure 1 of
the article by Wenzel et al. As the authors note,
the long-term adverse effects of macrolide use in
patients with COPD remain unknown, but clinicians should remain alert to the possibility of the
development of nontuberculous mycobacterial
disease in patients during prolonged use of azith
romycin prophylaxis.
Stephen J. Chapman, D.M.

Hospital Universitari de Bellvitge

Barcelona, Spain
carolgv75@hotmail.com
No potential conflict of interest relevant to this letter was reported.
1. Hsueh PR, Teng LJ, Lee LN, Yang PC, Ho SW, Luh KT. Ex-

tremely high incidence of macrolide and trimethoprim-sulfamethoxazole resistance among clinical isolates of Streptococcus
pneumoniae in Taiwan. J Clin Microbiol 1999;37:897-901.
2. Reinert RR, Reinert S, van der Linden MY, Cil MY, Al-Lahham A, Appelbaum P. Antimicrobial susceptibility of Streptococcus pneumoniae in eight European countries from 2001 to
2003. Antimicrob Agents Chemother 2005;49:2903-13.
3. Brown SD, Farrell DJ, Morrissey I. Prevalence and molecular
analysis of macrolide and fluoroquinolone resistance among
isolates of Streptococcus pneumoniae collected during the 20002001 PROTEKT US Study. J Clin Microbiol 2004;42:4980-7.
4. Albert RK, Connett J, Bailey WC, et al. Azithromycin for
prevention of exacerbations of COPD. N Engl J Med 2011;365:68998. [Erratum, N Engl J Med 2012;366:1356.]

Oxford Radcliffe Hospitals

Oxford, United Kingdom
schapman@well.ox.ac.uk
No potential conflict of interest relevant to this letter was reported.
1. Griffith DE, Aksamit T, Brown-Elliott BA, et al. An official

ATS/IDSA statement: diagnosis, treatment, and prevention of

nontuberculous mycobacterial diseases. Am J Respir Crit Care
Med 2007;175:367-416. [Erratum, Am J Respir Crit Care Med
2007;175:744-5.]
2. Levy I, Grisaru-Soen G, Lerner-Geva L, et al. Multicenter
cross-sectional study of nontuberculous mycobacterial infections among cystic fibrosis patients, Israel. Emerg Infect Dis
2008;14:378-84.
3. Renna M, Schaffner C, Brown K, et al. Azithromycin blocks
autophagy and may predispose cystic fibrosis patients to mycobacterial infection. J Clin Invest 2011;121:3554-63.
DOI: 10.1056/NEJMc1210335

DOI: 10.1056/NEJMc1210335

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