P. aeruginosa - BACTERIOWEB

Resistance of Pseudomonas aeruginosa to
Antibiotics
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P. aeruginosa, an opportunistic pathogen
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Important issues of P. aeruginosa therapy
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P. aeruginosa, an opportunistic pathogen
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5,570 genes

Natural resistance of P. a eruginosa
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Antipseudomonal antibiotics
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Wild-type drug susceptibility
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Natural resistance of P. a eruginosa
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Ticarcillin
Claventin
Pipéracillin
Tazocillin
Cefepime
Ceftazidime
Aztreonam
Imipenem
Ciprofloxacin
Tobramycin
Amikacin
/3 4
100
90
80
70
60
50
40
30
20
10
0
Drug susceptibility of P. aeruginosa in
France
(1994-2004)

Multidrug resistance in bacteremic strains
A B7 C
A B7 C
60
50
40
30
20
10
0
50.8
Multi-rˇsistance GESPA 2001
13.1 13.1
10.0
0 1 2 3 4 5 6 7
Nb d'atb I/R parmi Amk, Tob, Cip, Tzp, Caz, Tic, Imp
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60
50
40
30
20
10
0
50.8
3.1
Multi-rˇsistance GESPA 2001
14.6
16.2
6.2
11.5
3.8
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Nb d'atb I/R parmi 1 BL, 1AG, Cip, Imp
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Multidrug resistant strains
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100
90
80
70
60
50
40
30
20
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Drug susceptibility of P. aeruginosa in Iran
Ticarcillin
Claventin
Pipéracillin
Tazocillin
Cefepime
Ceftazidime
Aztreonam
Imipenem
Ciprofloxacin
Tobramycin
Amikacin
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1 / & $ 4 $ " GE F

Acquisition of resistance in P. aeruginosa
Foreign DNA
(plasmids, transposons, integrons)
Intrinsic mechanisms
•Genotypic (in vivo, in vitro): mutations, transpositions, IS
•Phenotypic (in vivo): lifestyle at the infection site
TREATMENT FAILURE

Resistance to ß-lactams
OprD
ß-lactamas e
PLP
MexAB-OprM
MexXY

Specific porin OprD and carbapenems
H 6 #E A I 3 C
H 6 4 J 4
H 6 3 3 9
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H / 3 6 > 3 E 7

Imipenem : consumption and resistance
+ > < 1 A % " %1 3> C

Resistance mechanisms to ß-lactams
(GERPA 2004)
Others
IPMase
NEM
Case + NEM
Case
Pase + Case
ESBL
Pase
No mechanism
0 10 20 30 40 50 60 70

Composite transposon Tn2345 carrying bla PER-1
ISPa23 ISPa24
tnpA1 (1,266-bp)
bla PER-1
6-bp direct repeats (duplication of the insertion site)
16-bp inverted repeats
tnpA2 (1,272-bp)
1kb
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RND efflux systems in P. aeruginosa
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Structure of efflux systems
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3 9 / - 3 " ?7DE MF

Contribution to intrinsic resistance in P. aeruginosa
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Efflux-mediated resistance to ß-lactams
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A &. @C

MexAB-OprM overproducing mutant
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modifying
enzyme
16S RNA
methylas e
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MexXY
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Resistance mechanisms to aminoglycosides
(Europe 1988-1993, n = 1,680)
GTNAI
GTN
GTNAI
GT
GTNAI
G
GTNAI
GTN
TNA
GTNAI
GTNAI
GTNAI
GTNAI
GTN
GN
GTNAI
GTN
GTN
GN
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Class I integron harbored by PA2345
1 kb
5’-CS
attC site :
gene cassettes
3’-CS
intI1 aad B orf E aad A 1 1 qa cE ∆∆∆∆ 1 sul 1 orf5
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Inverse core site Core site
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16S RNA methylases
+
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Efflux-mediated resistance to
aminoglycosides
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A &. @C

MexXY-overproducing mutant
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MexXY-mediated adaptive resistance
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Resistance to fluoroquinolones
DNA gyrase
(subunits A, B)
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GyrA ParC
GyrB
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MexAB-OprM
MexXY...
Topoisomerase IV
(subunits C, E)

Efflux-mediated resistance to quinolones
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A &. @C

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x 2 x 3 x 4 x 5
x 2 x 3 x 4
x 2 x 3 x 4 x 6
In vitro selection of efflux mutants
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Selection of mdr efflux mutants
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Emergence and loss of resistance in P. aeruginosa
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Emergence of MexAB-OprM efflux mutants
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Multidrug resistance
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Target/efflux mutants
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Multiple mechanisms
(69 bacteremic resistant strains 1999)
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Fighting multidrug resistance
Treatment
improvement
3 4
/
3
Hygiene measures

*
*
Conclusions
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Nightmare of the clinician

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