Mukoviszidose Lungeninfektionen: Pathophysiologie und Therapie · Gerd Döring, Institut für...
Transcript of Mukoviszidose Lungeninfektionen: Pathophysiologie und Therapie · Gerd Döring, Institut für...
Gerd Döring, Institut für MedizinischeMikrobiologie and Hygiene,
Universitätsklinikum Tübingen
Tübingen, 14. December, 2011
Mukoviszidose
Lungeninfektionen: Pathophysiologie und
Therapie
Pseudomonas Biofilm Formation
Pseudomonasbiofilm
Pseudomonasbiofilm
Pseudomonasbiofilm
Neutrophils
Pseudomonasbiofilm
Pseudomonasbiofilm
Pseudomonasbiofilm
Neutrophils
Worlitzsch et al. 2002
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Pseudomonas Transmission from the Environment to CF Patients
Sink CFU Air Hand1 1.4x107 - +2 2.1x108 +3 2.7x1010 +4 2.4x106 + 5 5.4x105 -6 5.2x1010 + +7 7.0x1010 + +8 1.0x1010 +
Döring et al., 1991
Döring et al., unpublished
Surveillance of P. aeruginosa Antimicrobial Resistance
% ResistantCF Isolates
Non-CF1 HPA 20032 BLT 20053 Mucoid Non-MucoidCiprofloxacin 20.2% 29.7% 49.3% 49.3% 49.4%Azlocillin - 38.9% 34.2% 43.1%Aztreonam - 36.4 % 25.3% 46.6%Gentamicin 22.9% 47% 35.5% 25.6% 44.2%Meropenem 10.8% 31.6% 24.5% 38%Imipenem 19% 31.5% 29.6% 33.3%Ticarcillin/clav - 28.8% 16.3% 41%Amikacin 16.6% 28.4% 18.4% 37.4%Ceftazidime 18.4% 39.6% 25.4% 22.3% 28.1%Pip/Taz 14.5% 31.9% * 23.3% 19.7% 26.4%Tobramycin 9.6% 10.1% 21.9% 14.4% 28.6%Colistin - 3.1% 0.9% 0% 1.7%
1MYSTIC Database 2Pitt et al, Thorax, 2003 3Soleimanian et al, ICAAC, 2006
Antibiotika-Therapie gegen Pseudomonas-Infektionen bei CF-Patienten
Bragonzi et al., 2005
50°C 4°C
Hermann et al. 2010
A
DC
BAA
DDCC
BB
Colistin Tobramycin
Colistin + Tobramycin Control
In vitro
P. a
erug
inos
aC
FU
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LBColistin Tobra Colistin/TobraP.
aer
ugin
osa
CFU
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LBColistin Tobra Colistin/Tobra
Hermann et al., 2010
Anti-entzündliche Therapie
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510 06
* 0,0298
* 0,0268
* 0,0246
BA
LF to
tal
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* 0,0268
* 0,0246
BA
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P. aeru + + + +0 0.3 50 100100 0Drug 0.3 50 100100
-
10 4
10 5
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10 9
** 0,0030
** 0,0097
ns
TOTA
L LU
NG
CFU
0Drug 0.3 50 10010 4
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10 9
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ns
TOTA
L LU
NG
CFU
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Döring et al., unpublished
Bragonzi et al., 2005
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% of infected mice p_______ ________________ _________
(mg/kg) blood spleen_________________________________________________
0 16 00.3 67 16 0.1
50 50 50 0.01100 57 50 0.005_________________________________________________
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Drug % of infected mice p_______ ________________ _________
(mg/kg) blood spleen_________________________________________________
0 16 00.3 67 16 0.1
50 50 50 0.01100 57 50 0.005_________________________________________________
Proteolytic damage and tissue remodeling in CF alveoli
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Age [years]
DES
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Ulrich et al. 2010
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Elas
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CF controls
CF controls020406080
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Aerosol α1-antitrypsin treatment for CF
McElvany Lancet 1991; 337:392–394
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M. Griese, personal information
Age
Patie
nts
%Age specific prevalence of bacterial organisms in CF airways
CF Foundation’s Patient Registry Annual Data Report 2009
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Staphylococcus aureus produces the exopolysaccharide PNAG in the lung of CF patients under anaerobic growth conditions
Ulrich et al, Mol
SrrA P
icaADBC
-O 2
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icaADBCicaR
SrrA P
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SrrA PSrrA P
icaADBC
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Ulrich et al, Mol Microbiol, 2007 Microbiol, 2007
0 min
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Increased prevalence of MRSA among CF patients in USA– 0.1% in 1995– 7.0% in 2001– 18.9% in 2006
Risk for CF patients to become MRSA-positive
1. Increased susceptibility for S. aureus colonization
2. Frequently treated with S. aureus-specific antibiotics
3. Frequently hospitalized
The anaerobes
1,00E+03
1,00E+04
1,00E+05
1,00E+06
1,00E+07
1,00E+08
1A 1B 3A 4A 4B 7A 7B 8A 8B 10A 10B 15A 15B 16A 16B 18A 19A 21A 22A 23A 24A 27A 28A 31A 33A 42A 44APatient and sample number
Tota
l Via
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Cou
nt (C
FU/g
)P. aeruginosa Anaerobe
Tunney et al. 2008
Stressmann et al. 2011
Median FEV1 Percent Predicted vs. Age, 1990 and 2009Pe
rcen
tPre
dict
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Age (Years)
CF Foundation’s Patient Registry Annual Data Report 2009
Pseudomonas Antibiotic Therapy
Ratjen et al. 2010
0102030405060708090
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1975 (n= 55)1980 (n=107)1985 (n=123)1990 (n=130)1995 (n=131)2002 (n=125)
0102030405060708090
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1975 (n= 55)1980 (n=107)1985 (n=123)1990 (n=130)1995 (n=131)2002 (n=125)
Mea
n∆
FEV 1
/yea
r
Chronic P. aeruginosa colonisationEarly eradication ∆FEV1/yr: -1.65%
∆FEV1/yr: -4.74% -14 -12 -10 -8
-6 -4 -2 0
Taccetti et al. Eur Respir J 2005; 26:1-4
Mea
n∆
FEV 1
/yea
r
Chronic P. aeruginosa colonisationEarly eradication ∆FEV1/yr: -1.65%
∆FEV1/yr: -4.74% -14 -12 -10 -8
-6 -4 -2 0
Taccetti et al. Eur Respir J 2005; 26:1-4
Vaccination against Pseudomonas
First Infection Chronic InfectionITT PP ITT PP
Verum 82 37 26 6
Placebo 105 59 29 12p 0.05 0.01 0.70 0.15NNT 11 11 100 32
Döring et al., 2007
483 CF Patients1997-2002 0
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Rec
ipro
cal t
iters
before 1 2 3 4 Placebo
CF and Ceramide CF
C CF C CF+ Amitriptyline
Cer
amid
e
C CF C CF+ Amitriptyline
Cer
amid
e
Teichgräber V et al., 2008 C CF C CF
+ AmitriptylineC CF C CF
+ Amitriptyline
Pseu
dom
onas
CFU
NO ? YES !
X-ray score of a CF patient who has received pulsed high-dose NO inhalation therapy. Left: before, right: after 2 days of 3 x 30 min of 100 ppm NO. Courtesy of Hubert Wirtz, Leipzig
Impact of gaseous NO on survival of microbes. Red: 200 ppm NO, blue: air. (Ghaffari A, 2006).
1. Die Zahl bakterieller Spezies in infizierten Atemwegen der CF Patienten hat sich erheblich vergrößert und umfasst viele strikteAnaerobier.
2. Antimikrobielle Resistenz der CF-spezifischen Pathogene nimmtzu.
3. Antibiotische Kombinationstherapie ist eine Alternative zurMonotherapie für chronische P. aeruginosa Infektionen.
4. Neben P. aeruginosa and S. aureus sollten möglicherweise auchstrikte Anaerobier antibiotisch behandelt werden.
5. Hochdosierte NO Therapie könnte Probleme mit resistentenBakterien lösen.
Zusammenfassung
1. Bessere anti-inflammatorischen Medikameente werden benötigt, jedoch stellt diese Therapie ein zweischneidiges Schwert dar.
2. Anti-Proteasen Therapie bleibt unbefriedigend.
3. Die Antibiotika-Frühtherapie hat die Lungenfunktion und die Lebenserwartung der Patienten erheblich gesteigert.
4. Die Vakzine-Entwicklung ist unbefriedigend
Zusammenfassung