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Fraunhofer Institute for Molecular Biology and Applied Ecology, Project Group Translational Medicine and Pharmacology, Frankfurt am Main, Germany
Institute of Pharmacology for Life Scientists, Goethe University Frankfurt, Frankfurt am Main, Germany
of Clinical Pharmacology, Goethe University Frankfurt, Frankfurt am Main, Germany
dFidelta d.o.o., Zagreb, Croatia
e4th Department of Internal Medicine, University of Athens, Medical School, Athens, Greece
fIntegrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
gBiomedical Research Division, Department of Theoretical and Applied Sciences, University of Insubria, Busto A., Varese, Italy
hDepartment of Basic Medical Sciences, Ghent University, Ghent, Belgium
iRespiratory Division, Lung Transplantation Unit, University Hospitals Leuven and Department of Clinical and Experimental Medicine, KU Leuven, Belgium
b
cInstitute
article
info
abstract
Azithromycin is a macrolide antibiotic which inhibits bacterial protein synthesis, quorum-sensing and reduces
the formation of biolm. Accumulating effectively in cells, particularly phagocytes, it is delivered in high
concentrations to sites of infection, as reected in rapid plasma clearance and extensive tissue distribution.
Azithromycin is indicated for respiratory, urogenital, dermal and other bacterial infections, and exerts
immunomodulatory effects in chronic inammatory disorders, including diffuse panbronchiolitis, posttransplant bronchiolitis and rosacea. Modulation of host responses facilitates its long-term therapeutic benet
in cystic brosis, non-cystic brosis bronchiectasis, exacerbations of chronic obstructive pulmonary disease
(COPD) and non-eosinophilic asthma.
Initial, stimulatory effects of azithromycin on immune and epithelial cells, involving interactions with
phospholipids and Erk1/2, are followed by later modulation of transcription factors AP-1, NFB, inammatory
cytokine and mucin release. Delayed inhibitory effects on cell function and high lysosomal accumulation
accompany disruption of protein and intracellular lipid transport, regulation of surface receptor expression, of
macrophage phenotype and autophagy. These later changes underlie many immunomodulatory effects of
azithromycin, contributing to resolution of acute infections and reduction of exacerbations in chronic airway
diseases. A sub-group of post-transplant bronchiolitis patients appears to be sensitive to azithromycin, as may
be patients with severe sepsis. Other promising indications include chronic prostatitis and periodontitis, but
weak activity in malaria is unlikely to prove crucial. Long-term administration of azithromycin must be balanced
against the potential for increased bacterial resistance. Azithromycin has a very good record of safety, but recent
reports indicate rare cases of cardiac torsades des pointes in patients at risk.
2014 Elsevier Inc. All rights reserved.
Abbreviations: AECOPD, acute exacerbations of COPD; AP-1, activator protein-1; ARDS, acute respiratory distress syndrome; AUC, area under the plasma concentration-versus-time
curve; BAL, broncho-alveolar lavage; BOS, bronchiolitis obliterans syndrome; CAD, cationic amphiphilic drugs; CAP, community acquired pneumonia; CBP, chronic bacterial prostatitis;
CF, cystic brosis; CFTR, CF transmembrane conduction regulatory protein; C max, peak plasma concentration; COPD, chronic obstructive pulmonary disease; COX, cyclo-oxygenase;
cPLA2, cytoplasmic phospholipase A2; DNFB, dinitrouorobenzene; DPB, diffuse panbronchiolitis; DTH, delayed type hypersensitivity; ERK, extracellular signal-regulated kinase; FGF, broblast growth factor; GM-CSF, granulocytemacrophage colony stimulating factor; GVH, graft versus host reaction; HR, hazard ratio; IL, interleukin; i.n, intranasal; i.p, intraperitoneal; i.t,
intratracheal; i.v, intravenous; JNK, c-Jun NH(2)-terminal kinase; LC3, microtubule-associated protein 1A/light chain 3; LOS, length of stay; LPS, bacterial lipopolysaccharide; LRTI, lower
respiratory tract infection; MAPK, mitogen-activated protein kinase; MDR1, multidrug resistance protein 1; MIC, minimum inhibitory concentration; MLSbK, macrolides, lincosamines,
streptogramin B and ketolides; MMP, metalloproteinase; MODS, multiple organ dysfunction syndrome; MPO, myeloperoxidase; MUC5AC, mucin 5AC; MV, mechanical ventilation;
NFB, nuclear factor kappaB; NGU, non-gonococcal urethritis; NK, natural killer cells; NR, not reported; OR, odds ratio; p.o, oral; PG, prostaglandin; PI, phosphatidylinositol; PI3K,
phosphoinositide-3-kinase; PK, pharmacokinetic; PMNL, polymorphonuclear leukocytes; PS, phosphatidylserine; RCT, randomized controlled clinical trial; ROS, reactive oxygen species;
SAA, serum amyloid A protein; SMC, smooth muscle cell; SREBP, sterol regulatory element binding protein; STAT, signal transducers and activators of transcription; STD, sexually transmitted disease; t1/2, plasma half-life; TLR, Toll-like receptor; T max, time to Cmax; TNF, tumor necrosis factor alpha; Th, T helper cell; VAP, ventilation assisted pneumonia; V d, volume of
distribution; VEGF, vascular endothelial growth factor.
Corresponding author at: Fraunhofer IME-TMP, Theodor-Stern-Kai 7, D-60596 Frankfurt am Main, Germany. Tel.: +49 69 6301 84234.
E-mail addresses: michael.parnham@ime.fraunhofer.de (M.J. Parnham), Vesna.ErakovicHaber@glpg.com (V.E. Haber), egiamarel@med.uoa.gr (E.J. Giamarellos-Bourboulis),
gianpaolo.perletti@uninsubria.it (G. Perletti), geert.verleden@uzleuven.be (G.M. Verleden), robin.vos@uzleuven.be (R. Vos).
http://dx.doi.org/10.1016/j.pharmthera.2014.03.003
0163-7258/ 2014 Elsevier Inc. All rights reserved.
226
M.J.M.J.
Parnham
Parnham
et al.et/ al.
Pharmacology
/ Pharmacology
& Therapeutics
& Therapeutics
143 143
(2014)
(2014)
225245
225245
Leclerq, 2002).Contents
In S. pyogenes there are three types of inducible
phenotype (a) iMLSbK-A, (b) iMLSbK-B, which is highly resistant to
azithromycin (MICN128 g/mL) and (c) iMLSbK-C with a medium resis1.Introduction
. . . . . .against
. . . . . . azithromycin
. . . . . . . . . . . . (Giovanetti
...
tance prole (MICs
up to 16 g/mL)
2.Antibacterial mechanisms of action . . . . . . . . . . . . . . . .
et al., 1999; Giovanetti
et al., 2002). In addition to methylation of
3.Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . .
23rRNA, resistance
can be achieved by mutation of various genes coding
4.Immunomodulatory activities . . . . . . . . . . . . . . . . . . .
for ribosomal components.
This type ofinresistance
been observed
5.Clinical applications
respiratoryhas
infections
and airway inammation
infrequently in S.6.Infections
pneumonia,ofS.thepyogenes
H.and
inuenzae,
the most infections .
urogenitaland
tract
sexually-transmitted
common mutations
occurring
in domain
V rRNA
7.Clinical
application
in sepsis
. . . and
. . . .proteins
. . . . . . . L4
. . . and
..
L22 (Tait-Kamradt
et al.,clinical
2000; Franceschi
8.Other
applicationset. .al.,
. . . 2004).
...............
Mef transporter9.Safety
(efux .pump)
. . . . . .expression
. . . . . . . . . .typically
. . . . . . . .results
. . . . . in a lower
10.Conclusions
. . . .14. . . and
. . . .15-membered
. . . . . . . . . . . . macrolide
....
level of specic resistance
towards
Conict
of
interest
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
. . .is. .referred
....
antibiotics (MICs 432 ug/mL) and this type of resistance
Acknowledgments
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
......
to as the M phenotype (Leclercq, 2002).
References
. . . . . . . . . antibiotics
. . . . . . . . . .is. .linked
. . . . . .with
. . . . an
Increased clinical
use of macrolide
increase in pneumococcal macrolide resistance. The Alexander Project,
monitoring antibiotic resistance among respiratory pathogens, reported
a global rate of pneumococcal macrolide resistance between 16.5% and
21.9% for 1996 and 1997 (Felmingham & Gruneberg, 2000), increasing
to 24.6% from 1998 to 2000 (M. R. Jacobs & Johnson, 2003). Over this
period, macrolide-exceeded penicillin-resistance in 19/26 countries.
The PROTEKT US surveillance study reported similar ndings. From
2000 to 2004, erythromycin resistance among S. pneumoniae isolates
1. Introduction
remained high (Jenkins et al., 2008), mef(A) being the most common
macrolide resistance genotype, accounting for N60% of tested isolates
Azithromycin,
a second
generation
(Farrell & Jenkins,
2004).
Althoughmacrolide,
macrolidebroad-spectrum
resistance rates have
antibacterial,
hasstabilized,
received increasing
attention
in recent
yearswith
because
subsequently
the prevalence
of clonal
isolates
a comof additional
effects
on
host-defence
reactions
and
chronic
human and
bined erm(B) and mef(A) genotype and a high-level
of macrolide
diseases.
It
is
the
prototype
15-membered
lactone
ring
azalide,
synthemultidrug resistance has increased.
sized Distribution
in the early 1980s
as a semi-synthetic
derivativevaries
of erythromycin.
of macrolide
resistance genotypes
between and
Discovered
around the
same
time by
researchers
at Pzer
in the
United
within countries.
In the
studies
mentioned
above,
highest
resistance
States
(Bright
&
Hauske,
1984)
and
at
PLIVA,
Croatia
(Kobrehel
al.,
rates were in Asia and some European countries (France, Italy, et
Spain,
1982),
PLIVAbeing
patented
rstand
and2560%,
licensed respectively.
the compound
to Pzer.resistance
Belgium),
N70%
Macrolide
With
much
improved
pharmacokinetic
over erythromycin,
was
common
among
S. pneumoniaeproperties
isolates (77.281.9%)
in Japan
azithromycin
became the
most
widely used
during PROTEKT
years
19992004,
the broad-spectrum
erm(B) genotypeantibacteaccounting
rialfor
in North
America.
Pzer
Inc's
Arthur
E.
Girard
and
Gene
Michael
most resistance (Inoue et al., 2008). In Portugal (19942002),
Bright,
togetherofwith
PLIVA's Slobodan
Djokic (posthumously)
andcorrelatemergence
macrolide-resistant
S. pneumoniae
strains clearly
Gabrijela
in 2000
American
Chemical
ed withKobrehel,
increasedreceived
azithromycin
usethe
(Dias
& Canica,
2004).Society's
awardInofaHeroes
of Chemistry
who have
promoted human
in
recent study
on commensal
Staphylococcus
aureuswelfare
in Europe,
the except
area offor
health
for their
of Zithromax
(azithromycin).
penicillin,
the discovery
highest recorded
resistance
rate was to
Azithromycin
the same
mechanism
antibacterial
azithromycin shares
(from 1.6%
in Sweden
to 16.of9%
in France) action
(den Heijer
as other
(Allen, 2002),
butclarithromycin
accumulates more
et al.,macrolide
2013). Asantibiotics
usage of azithromycin
and
has increased
effectively
in
phagocytes,
thus
being
delivered
in
high
concentrations
for indications beyond RTI, resistance has started to emerge in nonto sites
of
infection
(Miossec-Bartoli
et
al.,
1999;
Wilms
et
al.,
2006).
respiratory pathogens. For instance, macrolide treatment of healthy
It also
inhibits in
bacterial
quorum-sensing
reduces formation
volunteers,
comparison
to placebo, and
signicantly
increased of
the
biolm
and mucus
production, whichoral
extend
its range for
of antibacterial
proportion
of macrolide-resistant
streptococci
up to 180 days
actions
(Tateda
et
al.,
2001;
Hoffmann
et
al.,
2007).
As
an
antibiotic,
after treatment (Malhotra-Kumar et al., 2007). Consequently, as with
azithromycin
is indicated
for respiratory,
dermal
other
all antibiotics,
azithromycin
should beurogenital,
administered
for alland
relevant
bacterial
infections,
butconsideration
has benecialofeffects
in chronicbenets
inammatory
conditions
with due
the associated
and risks.
disorders such as diffuse panbronchiolits, bronchiolitis obliterans and
rosacea. Efcacy in these conditions is ascribed to immunomodulatory
effects on innate and adaptive immune responses. Modulation of host
response reactions also accounts, at least partially, for benecial effects
in cystic brosis, non-cystic brosis bronchiectasis, bronchial obliterans
syndrome (BOS) and chronic obstructive pulmonary disease (COPD).
Azithromycin is well-tolerated and has a very good record of safety.
Although macrolides have a class warning for potential cardiac QT prolongation, azithromycin does not show this effect under experimental
conditions (Milberg et al., 2002). Until recently, only a handful of cases
of QT prolongation had been reported for patients treated with the
drug (Kezerashvili et al., 2007). This is mainly because azithromycin,
unlike other macrolide antibiotics, does not interact with CYP3A4,
despite a minor interaction with the anti-coagulant warfarin (Kanoh
& Rubin, 2010; Mergenhagen et al., 2013). Recently, evidence for
increased risk of QT prolongation with azithromycin has appeared, but
mainly
in patients with greater susceptibility to adverse cardiac effects
3. Pharmacokinetics
(Giudicessi & Ackerman, 2013).
We review here the antibacterial actions and pharmacokinetics of
Early pharmacokinetic
(PK) studies on azithromycin,
low
azithromycin,
as well as its immunomodulatory
effects and indicating
the
plasma levels,
were in
incorrectly
interpreted
as reecting
poor PK propermechanisms
involved,
comparison
to other macrolide
antibiotics.
Azithromycin
is now uses
known
to have a largedrawing
volume attention
of distribution,
Weties.
discuss
the main clinical
of azithromycin,
achievingindications
high tissueand
concentrations
is its
efciently
delivered to sites
to emerging
emphasisingand
how
pharmacokinetic
of infection. Compared with older generation macrolides, it is more
stable in acidic media and has a longer half-life, allowing for once a
day or even single dose treatment (Amsden, 1995, 2001). Moreover,
azithromycin is barely metabolized, with no active metabolites and
does not induce CYPs (Amsden, 1995; Nightingale, 1997).
227
228
factors than drug metabolism are thought to account for serious adverse
effects seen with azithromycin (Fleet et al., 2013) (see Section 9).
PK parameters may be affected considerably by co-administration of
azithromycin with food, prolongation of Tmax, 50% reduction of Cmax,
and of AUC072h having been observed in fed, compared to fasting patients (Table 1) (Curatolo et al., 2011). Azithromycin pharmacokinetics,
in keeping with low hepatic metabolism, are not signicantly affected
by mild or moderate hepatic impairment or class-A or -B liver cirrhosis
(Mazzei et al., 1993), nor by mild or moderate renal insufciency
(Hofer et al., 1995; Singlas, 1995). PK parameters are also virtually
unchanged in patients with diabetes (Ernst et al., 2000). Hence, no
dose modications of azithromycin appear to be necessary in patients
suffering from these conditions. However, severe renal impairment
noticeably increases Cmax and AUC0120 (http://www.medicines.org.
uk/emc/medicine/26131). Interestingly, in such patients on permanent
peritoneal dialysis due to oliguric end-stage renal failure (Kent et al.,
2001), the Cmax of azithromycin increased but Tmax appeared to be in
the normal range.
Table 1
Azithromycin pharmacokinetic data extracted from a sample of studies published between the years 1996 and 2013.
Dose/route (mg)
Cmax (g/mL)
tmax (h)
AUC (gh/mL)
t1/2 (h)
Ke (h1)
Clplasma (L/h)
F (%)
Vd (L/Kg)
(Amsden, 1996)
500 IV
500 oral
1500 oral
500 oral
500 IV
500 oral
500 oral
0.21
2.5
1.27
1.46
13.1
0.54
11.2
8.2
0.46
2.92
3.05
0.27
89.5 L/Kg
109.2
3.40
0.7
11
50.2
0.00138
46.6
17.8
78.6
Cmax, peak plasma concentration; tmax, time- to Cmax; Ke, pharmacokinetic elimination constant; Cl, plasmatic clearance; F, oral bioavailability; Vd, distribution volume.
AUC, area under- (denite integral of-) the plasma concentration-versus-time curve
AUC024.
AUC0.
229
Table 2
Pharmacokinetic data for azithromycin administered in different oral formulations or in fasting vs. fed patients.
(Lucchi et al., 2008)
Dose/route
500 mg immediate
release oral
2 g extended
release oral
Cmax (mg/L)
tmax (h)
AUC024 (gh/mL)
Clplasma (L/h)
Vd (L)
0.39
4
3.1
0.94
4
10
500 mg IR oral
0.40
2
2.67
518
uid (3 h) and umbilical cord serum (12 h) (Ramsey et al., 2003). The
serum half-life in extremely preterm infants is shorter (58 h) than at
full term or in adults. Importantly, preterm infants, treated with
10 mg/kg intravenous azithromycin, appear to be overexposed (about
3.2-fold) to the drug compared to older children (age: 0.52 years)
(Jacobs et al., 2005; Hassan et al., 2011) and clearance is low (0.18 L/h
in 1 kg pre-term neonate vs 0.98 L/h/kg in older children). This may
be attributed to the immature biliary excretion pathways in preterm
neonates (Hassan et al., 2011).
In pediatric subjects (mean 24 months) given an immediate-release
formulation of azithromycin (30 mg/kg), plasma concentrations and
drug exposure were higher than in adults (Liu et al., 2011), necessitating
a dose adjustment (Table 1). When an extended release formulation
was administered to children, the Cmax was still elevated compared to
adult subjects, but the AUC024 was lower (Liu et al., 2011).
4. Immunomodulatory activities
Early studies on macrolide antibiotics and host defense revealed
inhibitory effects on neutrophils in vitro, on experimental inammation
(Culic et al., 2001) and particularly actions on cytokine release (Bartold
et al., 2013). While azithromycin was shown in the late 1980s to inhibit
inammation and lysosomal enzyme release in arthritic rats (Carevic &
Djokic, 1988), subsequent studies were carried out predominantly with
erythromycin, clarithromycin and roxithromycin. All macrolide antibiotics inhibit various standard models of inammation (Ianaro et al.,
2000; Culic et al., 2001; Ivetic Tkalcevic et al., 2012) and more recent
studies have sought to clarify immunomodulatory mechanisms in vivo
(Table 3) and at the molecular level.
2 g extended
release oral
2 g extended
release oral
0.72
3.5
7.87
122
0.4/0.2
2/4
103
1830
4.1.2. Leukocytes
In neutrophils, subsequent to its pronounced accumulation (see
Section 3.1), slow efux of azithromycin prolongs its effects on the
cells in vitro and in vivo (Bosnar et al., 2005; Culic et al., 2002). This
extensive intracellular retention of azithromycin, for up to 28 days in
human neutrophils after standard dosing, leads to initial stimulation
of neutrophil degranulation and phagocytosis-associated oxidative
burst, further contributing to its antibacterial activity (Culic et al.,
2002). Acute inhibitory effects of azithromycin include downregulation of neutrophil chemokine production (IL-8, GRO-, MPO);
late effects comprise attenuation of neutrophil oxidative burst responses, down-regulation of myeloperoxidase (MPO) production,
increased neutrophil apoptosis and attenuation of chemokine (IL-8)and leukotriene (LT)B4-dependent and chemokine-independent
neutrophil chemotactic responses by inhibition of transcription factors,
nuclear factor kappa-B (NF-B) and activator protein-1 (AP-1) (Culic
et al., 2001; Culic et al., 2002; Tamaoki et al., 2004; Tsai & Standiford,
2004). Azithromycin also inhibits prostaglandin (PG)E 2-synthesis by
suppressing expression of prostaglandin synthetic enzymes (COX-1
and COX-2) in both lipopolysaccharide (LPS)-stimulated polymorphonuclear leukocytes and monocytes (Miyazaki et al., 2003). In the latter,
azithromycin decreases tumor necrosis factor- (TNF-) and granulocytemacrophage colony stimulating factor (GM-CSF) production
(Khan et al., 1999).
In sputum cells (81.7% neutrophils, 12.9% monocytes/macrophages)
isolated from steroid-nave patients with COPD, azithromycin and
other macrolides inhibited, in a concentration-dependent manner,
the release of a variety of inammatory cytokines and chemokines
(Marjanovic et al., 2011). The macrolides were more broadly inhibitory
than the corticosteroid, dexamethasone, the PDE4 inhibitor, roumilast,
and the p38 kinase inhibitor, SB203580. Azithromycin was less effective
than clarithromycin and roxithromycin, but its broad inhibitory activity
may provide corticosteroid-sparing effects in treatment of respiratory
inammation (see Section 5.4). An extensive list of the effects of
azithromycin on cytokine production, generally, was published recently
(Bartold et al., 2013). Azithromycin inhibits neutrophilic inammation
in vivo induced by LPS given by various routes (Table 3). Lung
neutrophilia induced by intranasal LPS is inhibited by azithromycin in
association with a reduction in lung GM-CSF and IL-1, both of which
were also inhibited by azithromycin in macrophages in vitro (Bosnar
230
M.J.M.J.
Parnham
Parnham
et al.et/ al.
Pharmacology
/ Pharmacology
& Therapeutics
& Therapeutics
143 143
(2014)
(2014)
225245
225245
action of
azithromycin
on broblast
MPR300 (and/ordendritic
on membrane
et al.,
(Kanoh
2009).
&Subsequently,
Rubin, 2010; Shinkai
the action
et on
al.,lung
2008).
neutrophilia
Mainly based
was on
localized
studies on
complex
(MHC)
class II molecules
in LPS-stimulated
cells,
phospholipid
uidity)receptor
may account
for its
inhibitionIL-12
of theproduction
pinocytosis
to the
mucus
alveolar
and cytokine
macrophages
production
(Bosnar
byetairway
al., 2011).
epithelial and inammatory
and
attenuates Toll-like
(TLR)-4
expression,
ofallostimulatory
macromolecules
and their
transport potential
from the for
plasma
membrane
In
cells,
alveolar
the authors
macrophages,
concluded
azithromycin
that macrolide
attenuates
antibiotics,
LPS-induced
including
and
capacity,
suggesting
modulation
of to
endo/lysosomes
(Tyteca
et al.,et2001).
Acute
effects
on MPR300
production
azithromycin,
and expression
exert biphasic
of pro-inammatory
stimulatory thencytokines
inhibitorythrough
effects inhion
allogeneic
responses
(Iwamoto
al., 2011,
2013).
Animal
studies may
also explain
the paradoxical
by azithromycin
of lysosomal hybition
MAPK
of AP-1
kinase
(Bosnar
(ERK,etJNK,
al., 2011;
p38) Meyer
activity,etwith
al., 2009)
subsequent
(see Section
modulatory
4.2.4)efsuggest
that azithromycin
may increase
also modulate
Th2 cell responses
activity by
in broblasts
(Gerbaux et al., 1996)
the early
andfects
it inhibits
on NFB
arachidonate
and AP-1release
transcription
and metabolism
factor activities.
in LPS-stimulated
Crosstalk between
in drolase
vivo, probably
effects on antigen-presenting
cellsand
(Table
3). In-release
and prolonged
depletion
circulatingcould
neutrophil
enzymes
macrophages
ERK and p38
(Banjanac
was suggested
et al., 2012).
to cause
Azithromycin
mutually counteracting
increases phagoeffects.
duction
of a modulatory
DCofphenotype
explainlysosomal
ndings in
healthy
after volunteers
azithromycin
of human
volunteers
(Culic et
al.,IL-2
2002).
cytosis,
Azithromycin
probably and
by upregulating
to a less extent
the other
macrophage
macrolide
mannose
antibiotics,
receptor,
interacts
human
thattreatment
azithromycin
enhanced
proliferative
and
In
this
context,
inhibition
of
neutrophil
lysosomal
enzyme
release
CD206
with (Hodge
phospholipids
et al., 2008)
with pronounced
and makes lysosomes
effects on lysosomal
in macrophages
function and
receptor responses of blood mononuclear cells (MNC) to pokeweed by
neutrophils
was the
rst
anti-inammatory
more
these
resistant
must be
to oxidant
incorporated
challenge
into any
(Persson
consideration
et al., 2012).
of theAzithromycin
intracellular
mitogen
(Tomazic
et al.,
1993).
An inhibitoryeffect
effectof
onazithromycin
antigenever to be by
described
(Carevic
& Djokic,
1988).
alsoeffects
attenuates
of azithromycin.
T helper-1 cell (Th-1) responses following LPS or
presentation
DCs almost
certainly
explains
the Interestingly,
reduction by Niemann
Pick
C2
protein
(NPC2),
which
transports
cholesterol,
glycolipids and
interferon- (IFN-) stimulation of macrophages, shifting polarization
azithromycin pretreatment of the serum titre of specic anti-PCV7,
lysophosphatidic
acid immunized
out of lysosomes,
is also transported
to endo/
of activated macrophages towards the alternative/anti-inammatory
IgG1
antibodies in mice
with polyvalent,
polysaccharide,
lysosomes from
the Golgi
apparatus
by (Fernandez
MPR300 (Willenborg
et al.,
M2-phenotype, which plays a role in directing Th-2 responses and coorpneumococcal
conjugate
vaccine
(PCV7)
et al., 2004).
This
2005),also
so azithromycin
potentially
affect extra-lysosomal
lipid
dination of repair following inammation (Murphy et al., 2008a;
nding
indicates that could
treatment
of individuals
with azithromycin
transport.
In
fact,
expression
of
both
NPC1
and
NPC2
and
of
various
Yamauchi et al., 2009). Enhancement of M2-like macrophage generashould be avoided when an immunization procedure is planned.
Interactions
with
phospholipids
lysosomes of mice with
lipid
and cholesterol
metabolism
in human
cells was
tion4.2.1.
is observed
in vivo
after
azithromycinand
pretreatment
In human
natural killer
(NK) cellsgenes
stimulated
withepithelial
IL-15, azithroAzithromycin
and
other
macrolides
readily
penetrate
into
phosphoincreased
by incubation
with azithromycin
(Ribeiro et al., 2009).
Since
a cystic brosis-like disease (Legssyer et al., 2006).
mycin
inhibited
cytotoxic function
through down-regulation
of perforin
lipidmodulation
bilayers, the
of the desosamine
being inserted into has
the hydrolysophosphingolipids,
like azithromycin
Sections
4.1.2 and
4.3.5),
The
byN-3
azithromycin
of monocytes/macrophages
expression
(Lin et al., 2012).
Inammatory (see
cytokine
production
was
not
phobic
domain
andinthe
macrocycle
occupying
a position
at the
modify but
macrophage
differentiation
et al.,
2011), they
been
studied
in detail
classically
activated
human
blood monocytes
inhibited,
it was in the
transformed(Yamamoto
NK cell line,
NK-92.
hydrophobichydrophilic
interface
(Montenez
et
al.,
1996,
1999).
could
mediate
the
actions
of
azithromycin.
primed with IFN- and activated with LPS (Vrancic et al., 2012).
It should be noted that the pleiotropic effects of azithromycin are not
For azithromycin,
this position allows themanner,
positively-charged
Azithromycin,
in a concentration-dependent
distinctivelyamino
limited to a single anatomic site or organ or by the presence of microbes.
group
in
the
macrocycle
to
neutralize
the
negatively
charged
groups
inhibited the gene expression and/or release of M1 macrophage
For instance, azithromycin, like dexamethasone, inhibits the production
in the(CCR7,
phosphate
head ofand
theIL-12p70),
acidic phospholipids,
including
markers
CXCL11
but not TNF
or IL-6phosand enof the acute phase protein serum amyloid-A (SAA) during sterile inamphatidylinositol
(PI),
preferentially
found
at
the
inner
surface
of
the
hanced expression and/or release of M2 macrophage markers (IL-10
mation in mice (Glojnaric et al., 2007). SAA, like C-reactive protein
cell
membrane
bilayer
(Montenez
et
al.,
1999).
These
negatively
and CCL18), and the pan-monocyte marker CD163. Modulation of the
(CRP), is a pentraxin synthesized by hepatocytes after IL-1 or IL-6
charged
phospholipids
bind
signaling
proteins
to
the
inner
plasmaToll-like receptor (TLR) 4 signalling pathway, NF-kB and signal transstimulation, and can be inhibited indirectly by azithromycin through relemma
and
regulate
many
cellular
functions,
including
phagocytosis
ducer and activator of transcription-1 (STAT-1) activation were shown
duction of cytokine release at the inamed site. Nevertheless, given the
(Yeung
&
Grinstein,
2007).
Consequently,
neutralization
by
azithroto be involved. The inhibitory prole of azithromycin was similar to
strong accumulation of azithromycin in hepatocyte lysosomes, it may
mycin
of
the
negative
charge
could
conceivably
initiate
many
cellular
that of the lysosomotropic drug chloroquine, indicating that lysosomal
also directly inhibit hepatic pentraxin and cyto-/chemokine synthesis
effects.
4.2.2. Autophagy
accumulation of the macrolide played a crucial role (see Section 4.2.1).
(Matijasic
et al., 2012).
PI
contains
high
amounts
of
arachidonic
acid,
and
in
LPS-stimulated
Autophagy is a process whereby ubiquitin-tagged or HspIn dendritic cells, azithromycin modulates differentiation and LPSmacrophages,
azithromycin,
like
an
inhibitor
of
cytoplasmic
phospholichaperoned, often damaged, cytosolic components or intracellular
induced maturation towards a regulatory phenotype (e.g. enhanced
pasewith
A2 (cPLA2),
arachidonate
release and
eicosanoid
pathogens are engulfed in autophagosomes and transported to
IL-10)
increased inhibited
phagocytic
capacity (Polancec
et al.,
2012; production
but
not
cPLA2
expression,
probably
preventing
cPLA2
access
to
its
lysosomes for degradation (Randow & Munz, 2012). Fusion of
Sugiyama et al., 2007). Furthermore, azithromycin inhibits expression
membrane
substrates
(Banjanac
et
al.,
2012).
Reported
inhibition
by
autophagosomes with lysosomes is mediated by the delipidated
of co-stimulatory (CD40 and CD86) and major histocompatibility
macrolide antibiotics, including azithromycin, of arachidonate release
autophagy protein, microtubule-associated protein 1A/1B-light
and metabolism in LPS-stimulated neutrophils and mononuclear cells
chain 3 (LC3), which binds to phospholipids from apopototic parti(Miyazaki et al., 2003; Sato et al., 2007) was probably due to effects on
cles phagocytosed by leukocytes, thereby facilitating the engulfsignaling further downstream from TLR4.
ment of the resulting efferocytotic vesicles by lysosomes (Florey
Interaction of azithromycin with phospholipid head groups
& Overholtzer, 2012). In smooth muscle cells (SMC), azithromycin,
decreases their mobility and the uidity and elasticity of the plasma
at a clinically relevant concentration (10 M), induced autophagy
4.2.
Cell
signaling
processes
membrane (Fa et al., 2007; Tyteca et al., 2003), accounting for many
and
inhibited
actively
proliferating cells (Stamatiou et al., 2009).
effects of the macrolide on cellular functions. These include altered
This autophagy-mediated inhibition of SMC proliferation may
membrane insertion of markers into macrophage membranes and
contribute
to respiratory
effects of azithromycin.
The
mechanisms
of the immunomodulatory
actions of macrolide
slowing of their trafcking into lysosomes; inhibition of uid phase enIn contrast,
in broblasts
and human
macrophages,
azithromycin
antibiotics,
including
azithromycin
have been
reviewed previously
docytosis, but not phagocytosis, of macro-molecules; down-regulation
blocks autophagy, measured by accumulation of lipidated LC3 (LC3-II),
and delayed recycling of surface transferrin receptors, but not Fc reby reducing acidication of autophagosomes and lysosomes (Renna
ceptors (Tyteca et al., 2002, 2003). Moreover, anti-inammatory effects
et al., 2011). Particle-induced generation of TNF and intraTable
of3a range of synthetic macrolide derivatives on macrophages were
cellular mycobacterial killing by the macrophages was inhibited. In
Recent
studies onwith
the anti-inammatory/immunomodulatory
effects of azithromycin
in animal
correlated
their phospholipid binding properties
and number
of models in vivo.
cystic brosis (CF) patients treated for 6 months with azithromycin,
positively charged centers (Munic et al., 2011).
mycobacterial killing was also reduced and LC3-II increased (Renna
Reference
Model
Azithromycin dosing
Variables changed
Extensive lysosomal accumulation of azithromycin
results from
et al., 2011). The clinical signicance of this nding is questionable
proton-driven
concentration
of
its
dicationic
form
in
the
acidic
(pH
5)
lungstudy
leukocytes,
inammatory
cytokines,
on chronic
azithromycin
(Tsai et al., 2004)
Murine P.aeruginosa lung infection
s.c. from day 3 because, in a nested casecontrol
lysosomal milieu. Here, azithromycin, like other cationic amphiphilic
counts
treatment in a total of 27,112 not
CFbacterial
patients,
the longer the treatment
lung leukocytes, MPO,
drugs (CAD), inhibits lysosomal phospholipase A1 by blocking phoswith azithromycin, the less likely
were patients to have non(Legssyer et al., 2006)
CFTR-mutated mouse P.aeruginosa
p.o. 4 wks
lung M2-like macrophages
pholipid substrate access, causing phospholipidosis,
(Binder
et inammatory
al., 2013). cytokines,
lung infection the accumulation
Pretreatment tuberculous mycobacterial infections
lung bacterial
counts,
of phospholipids in lysosomes (Kosol et al.,
2012;
Van
Bambeke
et
al.,
Murine P.aeruginosa lung infection
s.c. from days 1 to Azithromycin
5
survival, lung
effects on autophagy
mayefferocytotic
depend onmacrophages
the intracel(Tsai
et al.,Phospholipidosis,
2009)
1996).
in turn, correlates with phospholipid binding
mortality,
lung
leukocytes,
lular site of action. Accumulation of azithromycin ininammatory
muscle cells is
cytokines, not bacterial counts
by a range of macrolide derivatives (Munic et al., 2011).
many-fold less than in broblasts
leukocytes,
in which
accumu lungand
leukocytes,
inammatory
cytokines,
not viral load
(Yamada
et al., 2013)
Murine
MDR for
A.baumanii
pneumonia
s.c. from days 1 to 6
Annother
mechanism of action may also
account
phospholation is predominantly lysosomal
(Matzneller et al., 2013). Effects
survival
lipidosis. Following phosphorylation of their mannose residues in the
lung leukocytes,
inammatory
cytokines,
on SMC, thus, may involve surface
membrane
effects, while
in the
(Beigelman
et al., 2010)lysosomal enzymes are transported
Murine Sendai to
virus
pneumonia by
s.c. from days 1 to 7
Golgi apparatus,
endosomes
other two cells, azithromycin may target predominantly lysosomal
(Tong
et al., 2011)
Murine Bacillus
pyocyaneus
shock
1 h before
the multifunctional
mannose-6-phosphate/insulin
growth
receptor
II
(Geudens et al., 2008)
Murine lung ischemiareperfusion
p.o. 14 days degradation processes. Macrolides bind with low afnity to
receptor, MPR300 (Kornfeld, 1992). Here,
the
acidic
endosome
environinjury
Pretreatment valosin-containing protein (VCP), a crucial mediator of intracellular
ment causes enzyme release and transfer Neonatal
to lysosomes,
while
MPR300
mouse lung
hypoxia
From days 1 to protein
10
degradation and autophagy (Ju & Weihl, 2010; Nujic et al.,
is returned
to the Golgi apparatus. All phospholipidosis-inducing
CAD
mortality,
lung leukocytes, inammatory 2012b; Tresse et al., 2010) which may account for some long-term
(Ballard
et al., 2007)
cytokines,
tested, including erythromycin, prevent MPR300 recycling from the
effects of azithromycin on autophagy.
(Terao et al., 2003)Murine i.p. LPS inammationi.g. 20 min lung NO, plasma NO & inammatory cytokines,
endosomes to the Golgi apparatus, causing lysosomal depletion and exRecently, azithromycin, clarithromycin and erythromycin
(Hao et al., 2013)Pretreatment plasma kynurenine & inammatory cytokines,
tracellular
secretion
of lysosomal
enzymes
(Ikeda30etminal.,
2008).
Such
an mortality
(Ivetic
Tkalcevic
et al., 2006)Murine
i.p. or i.v.
LPS shockp.o.
before
plasma
TNF,
were found to sensitize to cytotoxic and pro-apoptotic effects
(Bosnar et al., 2009; Bosnar et al., 2011) Murine i.n. LPS lung inammationp.o./i.p.4 h lung leukocytes, inammatory cytokines
of bortezomib by blocking autophagic ux in myeloma cells
PretreatmentIL-1 from alveolar macrophages
(Moriya et al., 2013), suggesting a potential use for macrolides
(Fernandez-Robredo et al., 2013)Rat subconjunctival LPS3 days topical pretreatment ocular inammation
in oncology.
(Glojnaric et al., 2007)Murine sterile s.c. AgNO3 inammation p.o. from 1 to 3 days plasma SAA & inammatory cytokines,
(Beigelman et al., 2009)Murine OVA asthmas.c. from 1 day before or after challenge lung inammation, BAL leucocytes & Th2 cytokines
(Ivetic Tkalcevic et al., 2012)Murine acute OXA skin DTHTopical after challenge ear edema, leukocytes, IL-4
Murine chronic skin DTH, repeated OXA Topical after each challenge ear mast cells, IgE, IL-4, not leukocytes,
(Plesko et al., 2010)Murine DNFB colon DTHFrom before or after challenge colitis
(Iwamoto et al., 2013)Murine allogeneic GvH diseasep.o. from day 2 to 2 graft resistance, due to effect on DCs?
(Fernandez et al., 2004)Murine immunization to pneumococcal i.p. 1 h before specic anti-PCV7 IgG1 antibodies
vaccine PCV7
CFTR: cystic brosis transmembrane conduction regulatory protein; DNFB: dinitrouorobenzene; GvH: graft versus host disease to transplanted bone marrow; i.g.: intragastric; i.n.:
intranasal; i.p.: intraperitoneal; i.v.: intravenous; MDR: multidrug resistant; MPO: myeloperoxidase; OVA: ovalbumin; OXA: oxazolone; p.o.: oral; s.c.: subcutaneous.
231
232
4.2.3. Apoptosis
Apoptosis is a crucial non-inammatory process for terminating the
life of cells, particularly immunocompetent cells. Interactions exist between apoptosis and autophagy in that the proteins, autophagy protein
5 (Atg5) and autophagy inducing protein, Beclin-1 are involved in both
processes (Fimia & Piacentini, 2010). It is, therefore, not surprising that
effects of azithromycin have been observed on apoptosis.
In SMC, azithromycin initially induces autophagy (Stamatiou et al.,
2009) and then apoptosis after prolonged incubation (Stamatiou et al.,
2010). At concentrations of 100 M or higher, azithromycin induces
apoptosis in neutrophils (Koch et al., 2000), an action shared by many
antibiotics (Healy et al., 2002); in human lymphocytes by inhibiting expression of Bcl-xL (Ishimatsu et al., 2004; Mizunoe et al., 2004); and in
NK cells (Lin et al., 2012). Induction of apoptosis is thus related to
prolonged, extensive accumulation, particularly at high doses, as seen
with circulating human neutrophils (Culic et al., 2002). This likelihood
is supported by studies on monocytes and macrophages.
Despite accumulating several hundred-fold in macrophages,
azithromycin does not readily induce apoptosis in these cells. To the
contrary, in human bronchial alveolar lavage (BAL) macrophages, lysosomal membrane permeabilization and ROS-induced cell death were
inhibited by long-term azithromycin treatment, an action conrmed
in vitro (Persson et al., 2012). Macrophages from azithromycin-treated
patients, in fact, show enhanced ability to phagocytose apoptotic cells.
First observed in patients with chronic obstructive pulmonary disease
(COPD), azithromycin in vitro restored to normal the reduced ability
of alveolar macrophages from COPD patients to phagocytose apoptotic
neutrophils (Hodge et al., 2006). Administered for 12 weeks to COPD
patients, the macrolide also enhanced alveolar macrophage efferocytotic capacity and mannose receptor (CD 206) expression, together
with a decrease in epithelial cell apoptosis (Hodge & Reynolds, 2012;
Hodge et al., 2008). This enhancement of macrophage efferocytosis is
now attributed to the ability of azithromycin to promote the expression
of the M2 macrophage phenotype (Section 4.1.2).
233
234
Phospholipid
bilayer penetration
Lysosomal
enzyme &
ROS release
Inflammatory
stimulus
Neutralizes negative
PLs, reduces FA release,
decreases membrane fluidity
MAPKs (ERKs)
Lysosomal
accumulation
Increased
phagocytosis?
Rac-1?
Lipid
remodeling
Surface
molecule
recycling
Phospholipidosis
SREBP1
AP-1
Lysosome
+LC3-II
NFB
High concs
+VCP
+ MPR
Autophagy
- Bcl
Enzymes
Apoptosis
Lipid
transport
Golgi
ER
Fig. 1. Effects of azithromycin on cell signaling. Azithromycin penetrates the cell membrane bilayer and stabilizes the membrane, reducing uidity. The cationic moiety of azithromycin
comes into close proximity to the negatively charged phospholipids in the inner leaet of the membrane, neutralising their charge. This results in reduced fatty acid release and also to
liberation of enzymes bound by electrostatic charge to the membrane. Lipid remodeling leads to modulation of signaling pathways, particularly of MAPK kinases, such as ERK1/2 (possibly
involving Rac-1) with subsequent inhibition of the activation of transcription factors including AP-1 and NFB. The signaling pathway most affected is likely to be dependent on the
particular cell, its activation state and the stimulus by which it is activated. Lysosomal enzyme release and initial induction of the oxidative burst of neutrophils are a consequence of
the actions on membrane lipids. Membrane lipid remodelling also disrupts surface molecule recycling and probably phagocytosis. Molecules dependent on negatively charged
phospholipids are also affected, including LC3-II, with subsequent inuences on lysosomal uptake and autophagy. The latter may also be inuenced, with time, by low afnity binding
of azithromycin to VCP. Azithromycin accumulates in lysosomes, modulating MPR transport of enzymes and lipids and through lipid remodeling in the lysosome membranes ultimately
leads to phospholipidosis. Apoptosis may be induced by high concentrations of azithromycin, possibly by compromising the action of the apoptosis inhibiting Bcl molecules. [ indicates
inhibition].
236
M.J.M.J.
Parnham
Parnham
et al.et/ al.
Pharmacology
/ Pharmacology
& Therapeutics
& Therapeutics
143 143
(2014)
(2014)
225245
225245
per5.2.
3 months
Diffuse
inpanbronchiolitis
comparison to a decrease of 0.10% per 3 months in the
placebo group (Altenburg et al., 2013). Macrolide resistance rate was
88% in azithromycin-treated individuals and 26% in the placebo group.
Initialwith
reports
on clinical
immunomodulation
byazithromycin
macrolides apIn children
non-CF
bronchiectasis,
once-weekly
for
peared
in the late
and 1990s,
whenexacerbations,
it became clear
the
up to
24 months
also 1980s
decreased
pulmonary
butthat
again
prognosis
of
patients
with
diffuse
panbronchiolitis
(DPB)
improved
drawith increased carriage of azithromycin-resistant bacteria (Valery
matically
implementing
treatment
with
macrolides.
et al.,
2013). after
Overall,
these RCTslong-term
conrm the
benecial
effects
with
This was rst
documented with
erythromycin,
demonstrating
signiazithromycin
or erythromycin
described
in prior, smaller,
retrospective
cant in
reduction
broncho-alveolar
lavage
(BAL)
of IL-1,
IL-8
studies
non-CF in
bronchiectasis
(Anwar
et al.,
2008;uid
Serisier
& Martin,
and Although
neutrophils
et al.,the
1996).
Sputumetiology
volumeof
in the
DPB
is reduced
2011).
not(Sakito
addressing
underlying
disease,
and lung function
by macrolides,
with marked
reduction of
azithromycin
may be improved
a therapeutic
option in patients
with frequent
neutrophil activation
lung
inltration,
of pro-inammatory
exacerbations
(Spagnoloand
et al.,
2013;
Suresh Babu
et al., 2013). cytokines and MMPs. This benet is seen despite the relatively high incidence of resistance to macrolides in Japan (Kobayashi et al., 1993;
Kudoh, 2004). Because of the established treatment of DPB with other
macrolides in Japan, azithromycin has been used less frequently, but
was recently reported to be effective and safe for long-term therapy
(Li et al., 2011).
Treatment of DPB is the most striking example of the introduction of
5.4.macrolide-therapy
Chronic obstructive
pulmonary
disease and
asthma
to chronic
respiratory
diseases.
However, the experience in DPB is almost exclusively based on non-randomized, controlled
clinical trials
(RCTs) or retrospective
studies (Kudoh
et al., antibi1998; Li et al.,
Short-term
azithromycin
has been an alternative
to rst-line
2011;
Yang
et al., 2013).
Drawing
on this of
experience
in DPB, long-term,
otics
in the
treatment
of acute
exacerbations
COPD (AECOPD)
for sevazithromycin therapy
subsequently
introduced
in CF
erallow-dose
years (Butorac-Petanjek
et al., was
2010;
Yamaya et al.,
2012). The
(Saiman
et al.,is2003),
bronchiectasis
(Anwar
2008),
benet
achieved
greaternon-CF
than with
other therapies
suchetasal.,
corticosteCOPD
(Blasi et al.,
2010; Hodge
al., 2008;
Parnham
et al., 2005),
roids
or roumilast
(Spagnolo
et al., et
2013).
Long-term
azithromycin
(Piacentini
et al.,
infectious
(Naidoo
bothasthma
decreased
frequency
of 2007),
exacerbations
andbronchiolitis
enhanced quality
of &
2009) though
and BOS
following
or hematopoietic
stem cell
lifeBryant,
in AECOPD,
with
a small lung
incidence
of hearing decrements
transplantation
(Gerhardt
et al., 2003;
et al.,
2008;toVos
et al.,
(Albert
et al., 2011).
Azithromycin
given Gottlieb
for several
months
patients
2010).
Clinical
evidenceefferocytosis
for immunomodulatory
effects and applicawith
COPD
also increased
in airway macrophages,
intions of
in inammatory
airway
is briey
dicating
an azithromycin
immunomodulatory
component
to its disorders
efcacy (Hodge
&
discussed
here based on landmark and important clinical trials.
Reynolds,
2012).
Azithromycin ameliorates bronchial hyperresponsiveness and airway neutrophil inltration in some children with asthma (Piacentini
et al., 2007), but failed to reduce rates of severe exacerbations and
LRTI in adult patients with severe asthma (Brusselle et al., 2013). Corticosteroids have limited efcacy in COPD or neutrophilic asthma and in a
subgroup analysis of patients with non-eosinophilic severe asthma,
azithromycin signicantly lowered rates of severe exacerbations and
LRTI requiring treatment with antibiotics (Brusselle et al., 2013).
Modulation of neutrophilic inammation probably accounts for these
ndings in asthma since azithromycin inhibits airway inammation in
a non-infectious, ovalbumin-induced mouse model of allergic asthma
(Beigelman et al., 2009) (see Section 4.3.3).
Despite broad inhibitory activity in experimental studies (see
Section 4.1), efcacy of azithromycin in clinical airways inammation
is limited. Clinical bronchodilatory effects have not been reported.
Azithromycin has a place in the treatment of COPD exacerbations, but
other than possibly contributing to corticosteroid-sparing in highly
selected patients, its potential role in the treatment of asthma remains
unclear (Spagnolo et al., 2013; Suresh Babu et al., 2013).
Cystic
brosis conditions
and non-cystic brosis bronchiectasis
5.6.5.3.
Other
respiratory
Macrolides
As in DPB,
(i.e.pulmonary
clarithromycin)
neutrophil
appear
inltration
to modulate
predominates
cryptogenic
in
organizing
patients with
pneumonia,
CF and radiation-related
non-CF bronchiectasis
bronchiolitis
and thisobliterans
encouraged
organizing
many investigators
pneumoniato(Mann
study et
azithromycin
al., 2005; Stover
in this&indication.
Mangino, In
2005)
an RCT
and
inpulmonary
251 patients
brosis
chronically
(Wuyts
infected
et al., 2010).
with P.This
aeruginosa,
is not surprising
standard 3 day
given
azithromycin
that in these
treatment
conditions,
weekly
the for
distal
24 airways
weeks signicantly
and alveoli initially
improved
may
FEV1
be involved
and reduced
in anrisk
inammatory
of exacerbations
process.
(Saiman et al., 2003). SubIn
sequently,
summary,when
numerous
treatment
pulmonary
was extended
disorders
to 12
sharing
months,
common
FEV1 remained
innate
unchanged
inammatory
in patients
mechanisms
not infected
canwith
potentially
P. aeruginosa,
benet from
although
the exaceranti-inammatory
bation and coughand
were
immunomodulatory
signicantly decreased
properties
(Clement
of azithromycin.
et al., 2006;
Azithromycin
Saiman et al.,
may,
2010).
therefore,
While prove
pulmonary
to be function,
a new milestone
thus, only
in the
improves
treatment
on azithromycin
of chronic pulmonary
treatmentdisorders,
for up to always
6 months
taking
and not
intothereafter,
account the
reincrease
duced in
exacerbations
macrolide resistance.
and reduced
In this
S. aureus
respect,
counts,
futurepresumably
development
related
of
non-antibacterial,
to immunomodulation,
anti-inammatory
are consistent
macrolide
ndingsderivatives
(Southern may
et al.,be2011).
crucial
The FEV1
(Bosnar
evolution
et al., 2012;
is explained
Kobayashi
by aetdecrease
al., 2013;inMencarelli
FEV1 during
et al.,
the initial
2011;
inammatory
Tomaskovic
phase,
et al.,which
2013)then
(Erakovic
increases
Haber
withetdecreasing
al., in press).
inammation after azithromycin is initiated, FEV1 subsequently reaching a
steady-state or plateau phase (depending on % predicted for each
individual). Azithromycin is generally considered an important part
of the treatment armamentarium for CF, particularly in patients chronically infected with P. aeruginosa (Spagnolo et al., 2013; Suresh Babu
et al., 2013).
6. Infections
urogenital in non-CF bronchiectasis is now well
The roleof
ofthe
azithromycin
tract
and sexually-transmitted
established
with three recentinfections
RCTs. In the EMBRACE trial, compared to
placebo, azithromycin decreased event-based exacerbation rates in
adult patients with non-CF bronchiectasis, whereas changes in FEV1
Over baseline
90% of an
dose oftotal
azithromycin
is excreted
via the
hepatofrom
andoral
in SGRQ
score during
the 6-month
treatment
biliary
system
(Ballow
et al., 1998;
al.,BAT
1990;
Singlas,
1995).
period
did not
differ (Wong
et al.,Foulds
2012). et
The
trial
conrmed
that
Since
drug is found
the urine,
is
dailyvery
uselittle
of azithromycin
forunchanged
12 monthsinresults
in a azithromycin
lower rate of innotfectious
suitableexacerbations
for diseases involving
signicant
bacteruria.
Due
to
its
optibut azithromycin also increased FEV1 by 1.03%
mal systemic distribution and tissue penetration, though, azithromycin
accumulates up to 100-fold in a variety of tissues of urological interest
(Foulds et al., 1990; Foulds et al., 1991).
6.1. Urethritis
Their considerable penetration into human cells makes macrolides
particularly suited for treatment of infections caused by obligate intracellular pathogens, like Chlamydia spp. For several years, azithromycin
has been the rst-line drug for treatment of primary non-gonococcal
urethritis (www.uroweb.org/gls/pdf/15_Urological_Infections.pdf),
mainly caused, in both sexes, by Chlamydia trachomatis, Ureaplasma
urealyticum or Mycoplasma genitalium.
Essential clinical evidence was provided in 1995 for this indication
in men (Stamm et al., 1995). A single 1 g oral dose of azithromycin,
for empirical treatment of acute non-gonococcal urethritis syndrome,
was as effective as a standard 7-day course of twice-daily 100 mg doxycycline in achieving clinical cure. Microbiological and overall clinical
cure rates with azithromycin were 83% and 81%, respectively (Stamm
et al., 1995).
A meta-analysis of RCTs conrmed the therapeutic equivalence of
the two regimens for chlamydial urethritis in men and women (Lau &
Qureshi, 2002). However, patient compliance to doxycycline for 7
days is often hampered by gastrointestinal side effects (Thorpe et al.,
1996). Since poor compliance is detrimental to resolution of the infection and may increase resistance, in our opinion, the 100% compliance
with a single-dose azithromycin regimen may minimize such risks.
Whereas azithromycin and doxycycline are equally active against
chlamydial infections, the macrolide achieved higher rates of eradication and clinical remission in patients with non-gonococcal urethritis
(NGU) caused by Mycoplasma genitalium (Falk et al., 2003; Mena et al.,
2009).
In women, chlamydial cervicitis/urethritis is highly prevalent, and
may occur concurrently with onset of preterm labor, preterm rupture
of membranes, spontaneous abortion, fetal death, postpartum endometritis, salpingitis, with risks to the neonate (Pitsouni et al., 2007). A single 1 g dose of azithromycin eradicates the infection in over 95% of cases
and is equivalent in terms of efcacy and symptom resolution to oneweek, once-daily 100 mg doxycycline (Thorpe et al., 1996). A metaanalysis (Pitsouni et al., 2007), involving 587 pregnant women, demonstrated high and equivalent efcacy of azithromycin, erythromycin and
Fig. 2. Proposed time course of azithromycin actions on infection and chronic inammation.
235
amoxicillin against chlamydial cervicitis/urethritis. However, azithromycin was associated with fewer gastrointestinal adverse events,
fewer total adverse events, and better compliance.
6.2. Prostatitis
Chronic bacterial prostatitis (CBP) is a difcult-to-eradicate biolm
disease, dramatically affecting quality of life and requiring long-term
antibacterial therapy for weeks or even months. Eradication of causative
pathogens is hampered by poor penetration of most antibacterial agents
into the prostate gland. Fluoroquinolones are currently the agents of
choice, due to adequate prostatic penetration, but recent RCTs show
that macrolides are becoming a primary therapeutic option for CBP
(Kolumbic Lakos et al., 2011; Magri et al., 2007, 2010; Skerk et al.,
2002, 2003, 2004, 2006). The rationale is the excellent penetration
and high concentration of this macrolide (see Sections 3.1 and 3.2) in
prostatic tissue and secretions, together with its powerful anti-biolm
and immunomodulatory activities. Consequently, azithromycin is
recommended as a therapeutic option for CBP in specic cases by
the European Urological Association (www.uroweb.org/gls/pdf/15_
Urological_Infections.pdf). The clinical and preclinical evidence
supporting azithromycin as a valuable treatment option for CBP has
been reviewed in detail (Perletti et al., 2011).
6.4. Glomerulonephritis
Crescentic glomerulonephritis is a severe renal complication of
infectious endocarditis, frequently caused by Gram-positive cocci or
Gram-negative Bartonella species (Kannan & Mattoo, 2001). The condition is not a urinary tract infection per se, but rather derives from immune activation by bacterial antigens. Bartonella endocarditis immune
complexes are deposited in the glomeruli cause necrotizing crescentic
glomerulonephritis. Interestingly, this form of glomerulonephritis may
improve with antibiotic therapy (Bookman et al., 2004). Resolution of
glomerulonephritis and normalization of serum creatinine levels was
achieved in several cases by aggressive therapy with azithromycin and
a parenteral cephalosporin (ceftriaxone) or by tobramycin/doxycycline
combination (Bookman et al., 2004). The efcacy of azithromycin
against facultative intracellular Bartonella may be explained by good
intracellular penetration of the macrolide (Massei et al., 2005).
It is estimated that severe sepsis and septic shock, mainly due to CAP,
annually affect 377 of 100,000 members of the general population;
mortality is 3550% making sepsis a leading cause of death, more common than malignancies and heart disorders (Kotsaki & GiamarellosBourboulis, 2012). Current guidelines recommend intravenous antibiotic treatment as early as possible, because with most antibiotic classes,
effectiveness decreases with time and sepsis severity (Dellinger et al.,
2013). Several retrospective analyses of prospectively collected data
have assessed the outcome of monotherapy over combination therapy
of severe CAP. The primary endpoint of these analyses was whether
inclusion of a macrolide (azithromycin, clarithromycin or erythromycin,
where recorded) in the combination affects mortality. The summary of
the seven studies published after 2006 is shown in Table 4. Four studies
indicated a signicant decrease in risk of death with the intake of one
macrolide (Martin-Loeches et al., 2010; Metersky et al., 2007; Restrepo
et al., 2009; Tessmer et al., 2009); two showed a signicant decrease in
duration of hospitalization (Ambroggio et al., 2012; Wilson et al., 2012);
and only one failed to show any benet (Karhu et al., 2013).
Two prospective, RCTs have evaluated the impact of macrolide
administration on the outcome of severe infections. In both trials, the
macrolide was clarithromycin, but in view of the striking outcomes,
they are discussed here as indicators of the potential use of other
macrolides, such as azithromycin. The hypothesis was that clarithromycin, administered at a dose of 1 g within 1 h on consecutive days,
should reach maximum serum levels (10 g/mL) sufcient to modulate
circulating monocyte function. In the rst study (GiamarellosBourboulis et al., 2008), 200 patients with ventilator-associated pneumonia (VAP) received placebo or clarithromycin for three days. Isolated
bacterial pathogens were multidrug-resistant species of Acinetobacter
baumannii, of Pseudomonas aeruginosa and of Klebsiella pneumoniae,
not included in the antimicrobial spectrum of clarithromycin. The
macrolide signicantly reduced by 5.5 days, time until resolution of
VAP (p = 0.011); by 6.5 days, time until weaning from mechanical
ventilation (p = 0.049); and the relative risk of death by septic shock
and multiple organ dysfunction (MODS; from 19.00 with placebo to
3.78 with clarithromycin; p = 0.048). No difference in incidence of
serious adverse events was seen.
Immunoparalysis develops during severe sepsis and drives towards
multiple organ dysfunction syndrome (MODS) and a lethal outcome
(Boomer et al., 2011). Crucially, clarithromycin treatment was accompanied by a reversal of immunoparalysis, most prominently 4 days
after start of treatment and among patients with septic shock and
MODS. Compared with placebo, clarithromycin decreased the serum
IL-10/TNF ratio; increased monocyte CD86 expression, a marker
of antigen-presentation efciency; and increased IL-6 production by
LPS-stimulated monocytes (Spyridaki et al., 2012). Reversal of immunoparalysis was unexpected as attenuation of inammatory responses in
patients would have been anticipated, based on the results of animal
studies with macrolides (Table 3). It seems that, like azithromycin,
clarithromycin can modulate monocyte function, depending on the
inammatory environment (see Section 4.1.2). Alternatively, these
ndings, at least in part, may represent an epiphenomenon arising
from improvement in the clinical course of sepsis following treatment.
In the second RCT study (Giamarellos-Bourboulis et al., 2013), 600
patients were enrolled with sepsis due to primary or secondary Gramnegative bacteremia, acute pyelonephritis or acute intrabdominal
infections, all with microbiologically-proven or clinically-suspected
Gram-negative bacteria insensitive to clarithromycin. Treatment was
extended to four days and the ndings of the rst RCT were conrmed.
Mortality due to septic shock and MODS was reduced by clarithromycin
to 53.6% compared to 73.1% with placebo (p = 0.020). Furthermore,
among patients with severe sepsis/shock, median time to infection
resolution was 6 days with clarithromycin and 10 days with placebo
(p = 0.037) and was accompanied by a signicant shortening of hospitalization time and reduction of costs. Treatment with clarithromycin
did not impact the safety of the patients.
237
238
M.J.M.J.
Parnham
Parnham
et al.et/ al.
Pharmacology
/ Pharmacology
& Therapeutics
& Therapeutics
143 143
(2014)
(2014)
225245
225245
Current
et al., 2013).
management
The benet
of sepsis
of long-term
remains macrolide
largely supportive.
treatmentTherapy
of DPB patargets
tients
theconsiderably
underlying infection
outweighsand
thisaims
concern,
to support
particularly
the function
since resistance
of
failing
to macrolides
organs. Allisagents
alreadydeveloped
high in Japan,
over the
where
last DPB
two decades
is demographically
that
inhibit
signicant
exaggerated
(see Section
pro-inammatory
5.2). In addition,
responses
the motilin-agonistic
have failed to prolong
effects
survival
of theorantibiotic
were even
result
harmful.
in an increased
The fact that
incidence
clarithromycin
of adverse
was
gastrointesable to
reverse
tinal the
effects
immunoparalytic
on prolonged state
treatment
arising
(Cameron
during severe
et al., sepsis,
2012). in
The
andevelRCT
opment
in patients
of novel,
withnon-antibacterial,
VAP (Spyridaki etnon-motilin
al., 2012), raises
receptor
hopes
binding,
that
macrolides,
immunomodulatory
including azithromycin,
macrolides may
mayovercome
offer a signicant
these concerns
advance in
the (Cameron
management
et al.,
of sepsis.
2012); Their
Erakovic
efcacy
Haberinetthis
al.,condition
in press).may
A further
help safety
explain
issuethe
with
benet
long-term
of macrolides
azithromycin
in patients
treatment
withisCAP.
the possible
The good
occurrence
efcacy
of azithromycin
in a small number
in severe
of patients
inammatory
of hearing
cases
defects
of post-transplantation
(Li et al., 2013).
bronchiolitis
For many
(see
years,
Section
azithromycin
5.5), suggests
has been
that there
one of
may
thebe
safest
similarities
broad
in the
spectrum
mechanisms
antibiotics.
involved
In contrast
in effects
to of
other
macrolides
macrolide
in antibiotics,
the two
not
conditions.
interacting with CYP3A4 means that it exhibits no metabolic interactions with most other commonly used drugs. It is N20-fold less potent
an inhibitor of hERG potassium channels than other macrolide antibiotics (Giudicessi & Ackerman, 2013). However, in an observational,
non-randomized study of patients enrolled into a Tennessee Medicaid
program, patients receiving azithromycin had an incidence of cardiovascular death 2.88-fold higher than those taking no antibiotic, and
8. Other clinical applications
2.49-fold higher than in patients on amoxicillin (Ray et al., 2012). Subsequently, the FDA introduced a black box warning about the potential
ofdisease
fatal arrhythmias with azithromycin, advising health profes8.1.risk
Skin
sionals to consider the risk of fatal heart rhythms with azithromycin
when considering treatment options for patients who are already at
Macrolide
antibiotics, are
widelyAused
for post-marketing
the topical treatment
risk for cardiovascular
events.
further
safetyofsurveilacne
and using
rosacea
and population-based
their use for thesehealthcare
and other databases
skin disorders
has
lance
seven
in Denmark,
been
reviewed
& Zedan,
2012).
In several among
small studies,
Italy,
and the(Alzolibani
Netherlands,
identied
azithromycin,
other medioralcations,
azithromycin
(for suspect
24 weeks)
provided
signicant
improvementacute
as a prime
for an
association
with drug-induced
in intractable
In one
healthy
volunteer-controlled
study, stanmyocardialrosacea.
infarction
(Coloma
et al.,
2013). The US observational
dard
dosing
azithromycin
4 weeks
to 17 patients
rosacea,
study
waswith
criticized,
though,for
because
Medicaid
patientswith
generally
reduced
score and
ameliorated
oxidave
burst
have ainammatory
higher comorbidity
than
patients inthe
theraised
general
population
(chemiluminescence)
of leukocytes
biopsies from
skinprospective
lesions
(Giudicessi & Ackerman,
2013). in
Importantly,
a large
study
(Bakar
et al.,to2007).
Since noDanish
microbiological
carried
in young
middle-aged
people at aanalyses
low-riskwere
of underlying
out,cardiovascular
it is unclear whether
the
effects
observed
were
due
to
antidisease revealed that the risk of cardiovascular death
inammatory
or treatment
antibacterial
rosacea
considered
due to 5-day
wasactions.
15.4 in Currently,
comparison
to 85.4isper
million
to be
a
disease
of
dysregulated
immunity.
In the absence
of 2013).
azithromycin courses in the innate
Tennessee
study (Svanstrom
et al.,
RCTs,
the
place
of
azithromycin
in
the
treatment
of
rosacea
remains
to
Thus, the risk of a cardiovascular event with azithromycin in otherwise
be established.
healthy patients is very small, but in patients at risk (i.e. idiopathic or
drug-induced baseline QT prolongation, familial long QT syndrome, or
multiple risk factors) azithromycin should be considered with care
and polypharmacy should be avoided (Giudicessi & Ackerman, 2013).
The
comparative
mechanismefcacy
of action
with
is considered
other drugs,toazithromycin
be a combination
is only
of recomantibacterial,
mendedimmunomodulatory
for use in DPB, CF,and
non-CF
biolm-inhibiting
bronchiectasiseffects,
and bronchiolitis.
associated
with Early,
the prolonged
mainly stimulatory
accumulation
effects
of azithromycin
of azithromycin
in inamed
on immune
tissues
and
(Wang,
epithelial
2010).
cells
The
areimproved
probablysafety
mediated
of azithromycin
by interactions
in comparison
with phosphoto
thelipids
current
andrecommended
Erk1/2. Later adjuvant
modulation
antibiotic
of transcription
treatmentfactors
with amoxiAP-1 and
cillin
NFB,
and is
metronidazole
accompaniedisbya further
inhibition
added
of inammatory
incentive to the
cytokine
introduction
and
of mucin
the macrolide.
release. Subsequent delayed inhibitory effects on cell function
are
Azithromycin
likely related
is widely
to the high
usedlysosomal
to treat gingival
accumulation
overgrowth,
of theamacrolide,
sideeffect
withofdisruption
cyclosporin
of protein
administration.
and lipidOnly
transport
3 RCTs
through
have the
beenGolgi
carried
apparaouttus
using
and aultimate
short treatment
effects on
period,
surface
butreceptor
clear reduction
expression,
of tissue
including
overgrowth
macrophage
was reported
phenotype
in allchanges,
studies and
anduse
autophagy.
of azithromycin
These later
for this
changes,
purpose
particularly
is recommended
on macrophage
(Hirsch
andetdendritic
al., 2012).
cell phenotype, appear to
underlie many in vivo experimental and clinical immunomodulatory
effects of azithromycin, contributing to resolution of acute infections
of the airways, genital tract and skin, as well as to reduction of exacerbation frequency in chronic airway diseases.
Immunomodulation with long-term azithromycin to reduce exacer8.3.
Ophthamology
bations
in COPD, CF and non-CF bronchiectasis patients must be
balanced against the potential for increased bacterial resistance. However, a sub-group of post-transplant bronchiolitis patients with proAzithromycin is used in ophthalmology for topical treatment of
minent neutrophil inltration appears to be particularly sensitive to
bacterial conjunctivitis and for off-label use in chronic blepharitis
long-term prophylactic therapy with azithromycin, as may be patients
(inammation of the eyelid) (Gebre et al., 2012). In the latter, applicawith severe sepsis treated acutely with the drug. Other promising indition of 1% azithromycin for 2 weeks reduced redness and swelling
cations include chronic prostatitis, rosacea and periodontitis.
and improved meibomian gland secretion (Luchs, 2010), probably
Although well-tolerated with a very good record of safety, azithrodue to immunomodulatory effects, also observed in a study of
mycin has recently been associated with rare cases of torsades des
topical azithromycin in LPS-induced ocular inammation in the rat
pointes in patients at risk of cardiac arrhymias and polypharmacy with
(Fernandez-Robredo et al., 2013).
azithromycin is generally to be avoided.
8.2. Dentistry
Over the last 20 years, a number of studies, only a few them RCTs,
have reported benecial effects of azithromycin in adjuvant treatment
of periodontal disease (Bartold et al., 2013; Hirsch et al., 2012). Microbiological studies indicate that azithromycin is highly effective against
Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans
(Bartold et al., 2013).
The balance of opinion is that azithromycin relieves infection and
inammation and reduces pocket depth, particularly in aggressive
forms of periodontal disease, but further controlled studies are needed.
10. Conclusions
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Table 4
mechanism
of action
as published
other macrolide
its range
of
Azithromycin
suppresses
activation of nuclear factor-kappa B and synthesis of proSummary
of retrospective
studied
after 2006 antibiotics
on the impact and
of macrolide
administration
on the outcome of community-acquired
pneumonia
(CAP).
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