infectiology award - uclouvain · cv 0.5 1.0 1.5 2.0 2.5 3.0 3.5 log 10 concentration (x mic) %...
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AWARDS 2013FOUNDATION
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ARDS 2013
Infectiology
award: Bacterial and cellular factors
affecting antibiotic activity towards persistent infections
Françoise Van Bambeke Louvain Drug Research
Institute, UCL
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Paul Ehrlich, the father
of anti‐infective
chemotherapy
15 December 2013 2
“corpora non agunt nisi fixata”
Ehrlich’s “magic bullet” theory
“The aim is to find chemical substances that have special affinities for pathogenic organisms and
that, like «magic bullets», go straight to their targets.”
AWARDS 2013FOUNDATION
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Studying
anti‐infective
pharmacology to improve
antibiotic
treatment
15 December 2013 3
bacteria host cells
antibiotic
patient
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Specific
lifestyles
associated with
persistent infections
15 December 2013 4
bacteria host cells
Seral
et al, AAC 1993
Intracellular
infection: an application of the Trojan
horse strategy
Intracellular
Staphylococcusaureus
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Specific
lifestyles
associated with
persistent infections
15 December 2013 5
bacterialresponsiveness
physico‐chemicalconditions
cooperation
with
host defences
accumulation and
bioavailability
metabolismbinding
influx
efflux
pharma
cokineti
cspharmacodynamics
bacteria host cells
Carryn
et al, Infect Dis
Clin
North Am., 2003
Intracellular
Staphylococcusaureus
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Specific
lifestyles
associated with
persistent infections
15 December 2013 6
bacteria host cells
Bauer, Siala
et al, AAC 2013
lifedead
Biofilms: bacterial
hibernation
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Specific
lifestyles
associated with
persistent infections
15 December 2013 7
bacteria host cells
Bauer, Siala
et al, AAC 2013
Biofilms: bacterial
hibernation
Gradient ofnutriments,oxygen
Gradient of
metabolic
activity
and viability
catheter, bone, skin, cardiac
valve, …life
dead
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Specific
lifestyles
associated with
persistent infections
15 December 2013 8
Lemaire et al, JAC 2011
-1 0 1 2 3 4 5-5
-4
-3
-2
-1
0
1
2
3
extraintra
log10 concentration (X MIC)
lo
g C
FU fr
om ti
me
0
Intracellular
infection: activity
of the fluoroquinolone
moxifloxacin
on S. aureus
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Specific
lifestyles
associated with
persistent infections
15 December 2013 9
Lemaire et al, JAC 2011
close to the MIC even
for antibiotics
accumulating
in cells
Cs ~ intracellular
bacteria
: Measure
of the «
intracellular
MIC
»
• «
Pharmacokinetic‐related
»
parameter:accumulation in the infected
compartmentintracellular
bioavailability
• influence of local environment
on activitypHoxidant
species
-1 0 1 2 3 4 5-5
-4
-3
-2
-1
0
1
2
3
extraintra
log10 concentration (X MIC)
lo
g C
FU fr
om ti
me
0
Intracellular
infection: activity
of the fluoroquinolone
moxifloxacin
on S. aureus
Cs
« rel. potency
»
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Specific
lifestyles
associated with
persistent infections
15 December 2013 10
Lemaire et al, JAC 2011
Lower
than
extracellularly, suggesting
poor
bacterial
responsiveness
and/or
antibiotic
expression of activity
Emax
~ intracellular
bacteria: Measure
of killing
capacity
• «
Pharmacodynamic‐related
»
parameter:mode of action of the drugbacterial responsivenesscooperation with host defenses
-1 0 1 2 3 4 5-5
-4
-3
-2
-1
0
1
2
3
extraintra
log10 concentration (X MIC)
lo
g C
FU fr
om ti
me
0
Intracellular
infection: activity
of the fluoroquinolone
moxifloxacin
on S. aureus
Cs
« rel. potency
»
Emax
«
efficacy
»
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Specific
lifestyles
associated with
persistent infections
15 December 2013 11
CT0
20
40
60
80
100
120
RFCV
0.5 1.0 1.5 2.0 2.5 3.0 3.5log10 concentration (X MIC)
% c
ontr
ol v
alue
Bauer, Siala
et al, AAC 2013
Emax
«
efficacy
»
C25
« rel. potency
»
Pharmacodynamic
profile similarto that
observed
intracellularly,suggesting
similar
defeating
factors
Biofilm: activity
of the fluoroquinolone
moxifloxacin
on S. aureus
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Active efflux and intrinsic/acquired resistance
to antibiotics
15 December 2013 12
patient
bacteria
antibiotic
+
low
permeability
+ constitutive active efflux
intrinsic
resistance
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Active efflux and intrinsic/acquired resistance
to antibiotics
15 December 2013 13
Azithromycin
is
inactive on P. aeruginosa
…
medium strain MIC (mg/L)
CA‐MHB PAO1 512
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Active efflux and intrinsic/acquired resistance
to antibiotics
15 December 2013 14
Azithromycin
is
inactive on P. aeruginosa
…
medium strain MIC (mg/L)
CA‐MHB PAO1 512
…
but is
successfully
used
in cystic
fibrosis
patients
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Active efflux and intrinsic/acquired resistance
to antibiotics
15 December 2013 15
Azithromycin
becomes
active on P. aeruginosa
when
efflux systems
are inactivated
Buyck
et al, CID 2012
medium strain MIC (mg/L)
CA‐MHB PAO1 512
PAO1
(mexAB‐oprM, mexCD‐oprJ,
mexJK, mexXY, mexEF‐oprN)
8
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Active efflux and intrinsic/acquired resistance
to antibiotics
15 December 2013 16
Azithromycin
becomes
active on P. aeruginosa
when
cultivated
in biological
fluids
Buyck
et al, CID 2012
medium strain MIC (mg/L)
CA‐MHB PAO1 512
PAO1
(mexAB‐oprM, mexCD‐oprJ,
mexJK, mexXY, mexEF‐oprN)
8
Bronchoalveolar
lavage PAO1 16
CA‐MHB/serum
50:50 8
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Active efflux and intrinsic/acquired resistance
to antibiotics
15 December 2013 17
Azithromycin
does
express its
activity
on P. aeruginosa
in biological
fluids
by repressing
the expression of its
efflux transporters
Buyck
et al, CID 2012
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Active efflux and intrinsic/acquired resistance
to antibiotics
15 December 2013 18
patient
bacteria
antibiotic
+
reduced
concentration at
the target
site
risk
of selection
of resistance
(target
mutations)risk
of suboptimal
dosage
+
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Active efflux and intrinsic/acquired resistance
to antibiotics
15 December 2013 19
Efflux mechanisms
are overexpressed
during
treatment
treatment
with
antibiotics
Pseudomonas
aeruginosa
isolated
from
patients in intensive care units
suffering
from
hospitally‐acquired
pneumonia
Riou
et al, ECCMID 2010
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Active efflux and modulation of cellular pharmacokinetics
of antibiotics
15 December 2013 20
patient
host cell
antibiotic
reduced
concentration inside
the cells
alteration
of activity
against
intracellular
bacteriamodification of PK profile
+
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Active efflux and modulation of cellular pharmacokinetics
of antibiotics
15 December 2013 21
Michot
et al., AAC 2004 & 2005
N
O
OH
O
HNN
F
N
C
O
FOH
O
OCH3
HN N
Differential
recognition of fluoroquinolones
by macrophage efflux transporters
ciprofloxacin
moxifloxacin
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Active efflux and modulation of cellular pharmacokinetics
of antibiotics
15 December 2013 22
Dupont
et al., ECCMID 2012
0 1 2 3 4 5 6 70
2
4
6
8
10
12
14
16R² = 0.8225
CIP
MXF
MIC change [NorA+/-] (fold dilutions)
Acc
umul
atio
n ch
ange
[Mrp
4+/-]
(fol
d)
But similarity
in recognition of fluoroquinolones
by macrophage and bacterial
efflux transporters
Substrates
of efflux systems
frommacrophages and Gram‐(+) bacteria
Poor
substrates
of efflux systems
frommacrophages and Gram‐(+) bacteria
24 FQ
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ASTRAZENECA AWARDS 2013
Studying
anti‐infective
pharmacology to improve
antibiotic
treatment
15 December 2013 23
bacteria host cells
antibiotic
patient
effluxefflux
intracellular
infection
?
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Cooperation
between
procaryotic
and eukaryotic
efflux systems
15 December 2013 24
Lismond
et al., AAC 2008
Bacterial
and eukaryotic
efflux pumps
cooperateto make
intracellular
Listeria monocytogenes
resistant
to ciprofloxacin
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Cooperation
between
procaryotic
and eukaryotic
efflux systems
15 December 2013 25
Moxifloxacin
intracellular
activity
is
not affected
by eukaryotic
/ bacterial
efflux pumps
Lismond
et al., AAC 2008
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Clinical
implications of this
work
15 December 2013 26
1.
Expression of activity is highly dependent on the environment•
Growth medium can influence bacterial physiology•
Intracellular bacteria / biofilms
are refractory to antibiotics importance of testing antibiotic activity in relevant media/models
2.
Screening tests in routine laboratories may need to be revisited•
Susceptibility changes during treatment•
Low level resistance mechanisms (efflux) often escape detection
in routine
but are clinically meaningful
interest of basing dosages on PK/PD approaches and MIC determinations
importance of developing new diagnostic tools
3.
Pertinent in vitro models may be helpful in preclinical evaluation of new drugs•
Intracellular survival is considered as determinant in recurrence /persistence•
Biofilms
are associated to about 80 % of infections in vitro screening may help selecting drug candidates
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Acknowledgments
15 December 2013 27
Financial support to this
work
Research
grants
from
pharmaceutical
companies
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Acknowledgments
15 December 2013 28
Coworkers over the years in the team ‐
efflux
+Laetitia
Avrain
Julien
Buyck Nancy
Caceres Hussein
Chalhoub
Farid
El Garch
Coralie
ValletMickaël
Riou Hariri
MustafaJean‐Michel
MichotBéatrice
Marquez
Ann
Lismond
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Acknowledgments
15 December 2013 29
Coworkers over the years in the team –
intracellular infections & biofilms
Julia
BauerEugénie
Basseres
Wafi
SialaNathalie
Vandevelde
Ahalieyah
AnantharajahMaritza
BarciaPierre
BaudouxJulien
Buyck
Stéphane
CarrynLaetitia
GarciaSandrine
LemaireHoang Anh
NguyenAurélie
Olivier
Youssef
OuadhririFrédéric
PeyrussonCristina
SeralSébastien
Van de Velde
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Acknowledgments
15 December 2013 30
Technical staff
Marie‐Claire
CambierCharlotte
MissonVirginie
Mohymont
Pierre
MullerKatia
SantosMartial
Vergauwen
The two
successive « heads »of the team
Paul
Tulkens
Marie‐Paule
Mingeot
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