Macrolide resistance in pneumococci—is it relevant?
Cheng and Jenney Pneumonia
Macrolide resistance in pneumococci-is it relevant?
Allen C. Cheng 0 1 4
Adam W. J. Jenney 2 3 4
0 School of Public Health and Preventive Medicine , Melbourne , Australia
1 Infection Prevention and Healthcare Epidemiology Unit , Melbourne , Australia
2 Microbiology Unit, Alfred Health , Melbourne , Australia
3 College of Medicine, Nursing and Health Sciences Fiji National University , Suva , Fiji
4 Department of Infectious Diseases, Monash University , Melbourne , Australia
Macrolide antibiotics are widely used for a range of indications, including pneumonia. Both high-level and low-level resistance to macrolides is increasing in pneumococci globally. Macrolide resistance in pneumococci is of limited clinical relevance where ß-lactams remain the mainstay of treatment, such as for moderate/severe pneumonia; however, data suggest that macrolides may not be able to be relied on as monotherapy for serious pneumococcal infections.
Streptococcus pneumoniae; Antibiotic resistance; Macrolides; Community-acquired pneumonia
-
Macrolide antibiotics, including clarithromycin and
azithromycin, remain an important class of antimicrobials
for pneumococcal diseases. In Australia, azithromycin is
recommended in combination with ceftriaxone as
empiric therapy for severe pneumonia, and clarithromycin
is a second line therapy for mild/moderate
communityacquired pneumonia. United States (US) guidelines are
currently being revised, but current recommendations
list macrolides as monotherapy for outpatient
pneumonia, and macrolides in combination with ß-lactams for
more severe pneumonia [
1
]. Although antibiotics are not
routinely recommended for otitis media, there is an
exception for high-risk children with otitis media (with
or without perforation), in which case azithromycin is
listed as one of several therapeutic options [
2
]. However,
the main selection pressure for resistant pneumococci
may come from its use in other indications such as
for non-pneumococcal respiratory tract infection [
3
],
bronchiectasis and chronic obstructive pulmonary
disease (COPD) [
4
], sexually transmitted diseases and
trachoma [
5
] (in different settings).
The increasing prevalence of macrolide-resistant
pneumococci has raised concerns about its place in
therapy. There are two major mechanisms mediating
resistance to macrolides. The ermB gene encodes a
methyltransferase that causes ribosomal methylation,
resulting in the macrolide-lincosamide-streptogramin B
(MLSB) phenotype that reduces susceptibility to
macrolides, lincosamide, and streptogramin B. This may be
expressed in a constitutive or inducible fashion [
6
]. mefA
codes for an antibiotic efflux pump removing the drug
from the target site. ermB tends to confer high level
resistance to macrolides with MICs >64 mg/l, whereas the
efflux mechanism results in lower MICs for erythromycin
(typically in the 1–16 mg/l range), compared to the
European Committee on Antimicrobial Susceptibility Testing
(EUCAST) breakpoint for erythromycin (and
clarithromycin and azithromycin) of 0.25 mg/l. Other resistance
mechanisms also exist, including the mefE variant efflux
pump carried on the macrolide efflux genetic assembly
(mega), mutations in 23S rRNA and also in the L4 and
L22 proteins, and the rare ermA methyltransferase [
7
].
There are significant global differences in susceptibility
and the mechanisms of resistance. The highest rates of
resistance have been reported in East Asia (particularly
China, Japan, and South Korea) [
8–10
] and rapid increases
in resistance are occurring in Malaysia [
11
]. Globally,
ermB methyltransferase is more common, but the
proportion of isolates carrying this gene was higher in several
European countries, and less common in North America
[
12
]. Co-existence of both ermB and mefA is relatively
common in some settings. It has been reported at 15 % in
South Africa [
13
], but as high as 38 % in Russia and nearly
50 % in Vietnam [
9
].
Because of the association between resistance and
pneumococcal serotypes, conjugate pneumococcal
vaccination has impacted on the epidemiology of resistance.
In some places the 7-valent vaccine has been shown to
cause a significant and lasting decline in macrolide
resistance through reduction in carriage and disease due to
serotypes 6B, 9 V, 19 F and 23 F that can carry the erm or
mef genes [
14, 15
]. While the concerns about replacement
with drug-resistant non-vaccine serotypes such as 19A
have mostly been addressed by the 13-valent vaccine,
replacement with other non-vaccine serotypes and capsular
transformation remains a concern [
16–19
].
Newer macrolides are concentrated intracellularly, and
this is thought to result in increased drug delivery to the
site of infection, and exposure to high concentrations of
drug following phagocytosis, which may overcome low
level resistance [
20
]. However, it has been suggested that
high-level resistance may be clinically relevant [
2 (...truncated)