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Recentadvancesonthetreatment
ofNFGNBinfections
Li Guanghui MD PhD
Huashan Hospital, Fudan University
2
BAD BUG,NO DRUG,NO ESKAPEE EE E nterococcus nterococcus nterococcus nterococcus S SS S taphylococcustaphylococcustaphylococcustaphylococcusK KK K lebsiella lebsiella lebsiella lebsiella A AA Acinetobacter cinetobacter cinetobacter cinetobacter P PP P seudomonas seudomonas seudomonas seudomonas E EE E nterobacter nterobacter nterobacter nterobacter
3
Importance of non-fermenters Non-fermenting gram-negative bacilli (non-
fermenters) include: Pseudomonas aeruginosa
Acinetobacter spp.
Stenotrophomonas maltophilia
Alcaligenes spp.
Burkholderia spp
Flavobacterium (Chryseobaterium ) spp. , et al
Non-fermenters are highly resistant to commonlyused antimicrobials
The infections of non-fermenters are difficult totreat with high mortality
Percentage of non-fermenters in Gram-negative bacilli in Shanghai,1991-2008(Wang F, et al. Int J Antimicrob Agents 2003; 22: 444)
4
146 0 1 632 1215 1171 136 9 16 61 2028 3028 327 5 3005 5242 565 6 48 18 58 19 5 665 6616YearYear
26262626
25252525
26262626
23232323
28282828
3030303 0 3 0303030
32323232
3434343 4 3 43434343535353 5 3 5353535
33333333
3434343435353535
33333333
34343434
36363636
20202020
22222222
24242424
26262626
28282828
30303030
32323232
34343434
36363636
38383838
1 9 9 1
1 9 9 1
1 9 9 1
1 9 9 1
1 9 9 2
1 9 9 2
1 9 9 2
1 9 9 2
1 9 9 3
1 9 9 3
1 9 9 3
1 9 9 3
1 9 9 4
1 9 9 4
1 9 9 4
1 9 9 4
1 9 9 5
1 9 9 5
1 9 9 5
1 9 9 5
1 9 9 6
1 9 9 6
1 9 9 6
1 9 9 6
1 9 9 7
1 9 9 7
1 9 9 7
1 9 9 7
1 9 9 8
1 9 9 8
1 9 9 8
1 9 9 8
1 9 9 9
1 9 9 9
1 9 9 9
1 9 9 9
2 0 0 0
2 0 0 0
2 0 0 0
2 0 0 0
2 0 0 1
2 0 0 1
2 0 0 1
2 0 0 1
2 0 0 2
2 0 0 2
2 0 0 2
2 0 0 2
2 0 0 3
2 0 0 3
2 0 0 3
2 0 0 3
2 0 0 4
2 0 0 4
2 0 0 4
2 0 0 4
2 0 0 5
2 0 0 5
2 0 0 5
2 0 0 5
2 0 0 6
2 0 0 6
2 0 0 6
2 0 0 6
2 0 0 7
2 0 0 7
2 0 0 7
2 0 0 7
2 0 0 8
2 0 0 8
2 0 0 8
2 0 0 8
P e r c e n t a g e ( % )
P e r c e n t a g e ( % )
P e r c e n t a g e ( % )
P e r c e n t a g e ( % )
上海地区糖非发酵菌中3个主要菌种的构成比变迁
5351
48
42
47
39 40
43
38
36
4042
41
28
21
29 2928
26 27 27
34
31
33
35 35
3
7 7 8 8
11 11
9 1 0 10
12 12 12
0
10
20
30
40
50
60
1 9 9 61 9 9 61 9 9 61 99 6 1 99 71 9 9 71 9 9 71 99 7 1 99 81 9 9 81 9 9 81 99 8 1 99 91 9 9 91 9 9 91 99 9 2 00 02 0 0 02 0 0 02 00 0 2 00 12 0 0 12 0 0 12 00 1 2 00 22 0 0 22 0 0 22 00 2 2 00 32 0 0 32 0 0 32 00 3 2 00 42 0 0 42 0 0 42 00 4 2 00 52 0 0 52 0 0 52 00 5 2 00 62 0 0 62 0 0 62 00 6 2 00 72 0 0 72 0 0 72 00 7 2 00 82 0 0 82 0 0 82 0 0 8
铜绿假单胞菌 铜绿假单胞菌 铜绿假单胞菌 铜绿假单胞菌 不动杆菌属 不动杆菌属 不动杆菌属 不 动杆 菌属 嗜 麦芽 窄食单 胞菌 嗜麦芽窄食单胞菌 嗜麦芽窄食单胞菌 嗜麦芽窄食单胞菌
铜绿假单胞菌呈下降趋势铜绿假单胞菌呈下降趋势铜绿假单胞菌呈下降趋势铜绿假单胞菌呈下降趋势
不动杆菌属呈上升趋势不动杆菌属呈上升趋势不动杆菌属呈上升趋势不动杆菌属呈上升趋势
嗜麦芽窄食单胞菌趋于稳定嗜麦芽窄食单胞菌趋于稳定嗜麦芽窄食单胞菌趋于稳定嗜麦芽窄食单胞菌趋于稳定
6
High incidence of non-fermentersin Gram-negative bacilli
45% (6686/15244) of GNB were non-fermenters
in CHINET (Resistance surveillance network in
China) surveillance program in China in 2005
(Wang F. Chin J Infect Chemother 2006; 6: 289)
Non-fermenters increased from 41% in 1999 to
48% in 2001 in ICU clinical isolates of GNB inNPRS (Nosocomial Pathogens Resistance
Surveillance) study program in China(Wang H, Chen MJ. Natl Med J China 2003; 83:385)
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华山医院2009年4588株细菌分布情况
7 8
Major Trends in Susceptibility
Pseudomonas: Substantial losses of
imipenem and ciprofloxacin susceptibilityinternationally
Acinetobacter: Carbapenem resistantorganisms now endemic in many ICUs (butvirulence generally not high)
Resistance to ceftazidime and imipenem among P. aeruginosaisolates collected in association with ICU-acquiredinfections,1986-2004.
9Clinical Infectious Diseases 2005; 41:848–54
SENTRY Program data for MDR P.aeruginosafrom bloodstream isolates (1997–2001).
10International Journal of Antimicrobial Agents 29 Suppl. 3 (2007) S33–S41
11
BSAC bacteraemia surveillance data for Pseudomonas
aeruginosa, 2002–2005 for the UK and Republic of Ireland.
12
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13
Resistance in P. aeruginosa, Shanghai 2000-2007(%)
0000
5555
10101010
15151515
20202020
25252525
30303030
35353535
2000200020002 00 0 2 00 1200120012 00 1 2 00 2200220022 00 2 2 00 3200320032 00 3 2 00 4200420042 00 4 2 00 5200520052 00 5 2 00 6200620062 00 6 2 00 7200720072007
Cefoperazone/sulbactamCefoperazone/sulbactamCefoperazone/sulbactamCefoperazone/sulbactam CeftazidimeCeftazidimeCeftazidimeCeftazidime ImipenemImipenemImipenemImipenem pip/tazopip/tazopip/tazopip/tazo
14.8
18.2 19.7 20.3
23.9 24.1 25.2
29.9 30.5
41.1
0
10
20
30
40
50
60
A m i k a c i n
A m i k a c i n
A m i k a c i n
A m i k a c i n
C P Z / S U L
C P Z / S U L
C P Z / S U L
C P Z / S U L
C e f e p i m e
C e f e p i m e
C e f e p i m e
C e f e p i m e
C e f t a z i m e
C e f t a z i m e
C e f t a z i m e
C e f t a z i m e
C i p r o f l o x a c i n
C i p r o f l o x a c i n
C i p r o f l o x a c i n
C i p r o f l o x a c i n
P I P / T A Z
P I P / T A Z
P I P / T A Z
P I P / T A Z
M e r o p e n e m
M e r o p e n e m
M e r o p e n e m
M e r o p e n e m
A z t r e o n a m
A z t r e o n a m
A z t r e o n a m
A z t r e o n a m
I m i p e n e m
I m i p e n e m
I m i p e n e m
I m i p e n e m
T C / C L
T C / C L
T C / C L
T C / C L
R e s i s t a n c e
R e s i s t a n c e
R e s i s t a n c e
R e s i s t a n c e ( % )
( % )
( % )
( % )
Resistance in P. aeruginosa ,,,,CHINET 2009 (n=4912)
Wang Fu, etal. CHINET 2009 surveillance of bacterial resistance in China. Chin J Infect Chemo 2010,10:325-334
0
10
20
30
40
50
60
70
80
1986 1988 1990 1992 1994 1996 1998 2000 2002 2004
P r o p o r t i o n
R e s i s t a n t
Amikacin Ceftazidime Imipenem
Antimicrobial Resistance among Acinetobacter sp.,From ICUs 1986-2003*
*Source: NNIS SystemClinical Infectious Diseases 2005; 41:848–54
BSAC bacteraemia surveillance data for A.baumannii , 2002–2005
16
17
Resistance in Acinetobacter sp, Shanghai 1999-2008 (%)
r e s i s t an c e %
5555 5555
4444 3333 33332222
4444 4444
10101010
16161616
21212121
27272727
33333333
40404040 40404040
46464646
4040404038383838
43434343
45454545
5050505048484848
5353535355555555
22225555
66668888 9999
1414141412121212
8888
11111111
19191919
24242424
20202020
27272727
3030303032323232
37373737
4444444446464646 47474747
0000
10101010
20202020
30303030
40404040
50505050
60606060
1995199519951 99 5 1 99 8199819981 99 8 1 99 9199919991 99 9 2 00 0200020002 00 0 2 00 1200120012 00 1 2 00 2200220022 00 2 2 00 3200320032 00 3 2 00 4200420042 00 4 2 00 5200520052 00 5 2 00 6200620062 00 6 2 00 7200720072 00 7 2 00 8200820082008
imipenemimipenemimipenemi m i pe n e m c e f ta z i di m eceftazidimeceftazidimec e f ta z i di m e C P Z/ S U LCPZ/SULCPZ/SULC P Z/ S U L P I P/ T A ZOPIP/TAZOPIP/TAZOPIP/TAZO
Resistance in Acinetobacter sp, CHINET
31.531.531.531.5 30.930.930.930.935.335.335.335.3
48.148.148.148.1 50505050
25252525
11.611.611.611.6
5.35.35.35.3
14.614.614.614.6
23.623.623.623.6
0000
10101010
20202020
30303030
40404040
50505050
60606060
70707070
2005200520052 005 2 006200620062 00 6 20072007200720 07 2008200820082008 2009200920092009
Imipenem
CPZ/SULR
E
S
I
S
T
A
N
C
E
%
18
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19
Resistance in Acinetobacter sp, CHINET 2009(%)
22.5 23.6
49 49.4 50 52.4
56.2 57.7 58.563
0
10
20
30
40
50
60
70
80
90
100
M i n o c y c l i n
M i n o c y c l i n
M i n o c y c l i n
M i n o c y c l i n
C P Z / S U L
C P Z / S U L
C P Z / S U L
C P Z / S U L
A M / S B
A M / S B
A M / S B
A M / S B
A m i k a c i n
A m i k a c i n
A m i k a c i n
A m i k a c i n
I n i p e n e m
I n i p e n e m
I n i p e n e m
I n i p e n e m
M e r o p e n e m
M e r o p e n e m
M e r o p e n e m
M e r o p e n e m
C e f t a z i d i m e
C e f t a z i d i m e
C e f t a z i d i m e
C e f t a z i d i m e
C e f e p i m e
C e f e p i m e
C e f e p i m e
C e f e p i m e
P I P / T A Z
P I P / T A Z
P I P / T A Z
P I P / T A Z
C i p r o f l o x a c i n
C i p r o f l o x a c i n
C i p r o f l o x a c i n
C i p r o f l o x a c i n
R e s i s t a n c e
R e s i s t a n c
e
R e s i s t a n c
e
R e s i s t a n c e ( % )
( % )
( % )
( % )
Wang Fu, etal. CHINET 2009 surveillance of bacterial resistance i n China. Chin J Infect Chemo 2010,10:325-334
Acinetobacter isolatesresistant tocarbapenems MYSTIC 2004
Countries that have reportedan outbreak of carbapenem-resistant Acinetobacterbaumannii. Red signifies
outbreaks reported before 2006, and yellow signifiesoutbreaks reported since 2006.
21
Antimicrobial resistance in S.maltophilia , CHINET(%)
19.1
10.6
20.1
2.9
16.3
12.9
11.4
1.5
17.8
12.111.7
2
15.1
12.413.2
1.8
0
5
10
15
20
25
CPZ/SB LEVO SMZ/TMP MINO
2 00 5 20 072 00 8 20 09
2005 n=877, 2007 n=1180, 2008 n=1310, 2009 n=1656
Antimicrobial resistance in S.maltophilia , CHINET 2009(%)
Antimicrobial agentsAntimicrobial agentsAntimicrobial agentsAntimicrobial agentsS.maltophiliaS.maltophiliaS.maltophiliaS.maltophilia((((n=1656n=1656n=1656n=1656))))
resistantresistantresistantresistant suceptiblesuceptiblesuceptiblesuceptible
CefoperazoneCefoperazoneCefoperazoneCefoperazone////sulbactamsulbactamsulbactamsulbactam 15.115.115.115.1 62.262.262.262.2
LevofloxacinLevofloxacinLevofloxacinLevofloxacin 12.412.412.412.4 83.183.183.183.1
SMX/TMPSMX/TMPSMX/TMPSMX/TMP 13.213.213.213.2 83.083.083.083.0
MinocyclineMinocyclineMinocyclineMinocycline 1.81.81.81.8 83.583.583.583.5
Wang Fu, etal. CHINET 2009 surveillance of bacterial resistance in China. Chin J Infect Chemo 2010,10:325-334
Antimicrobial resistance in Burkholderia spp(n=304) , CHINET 2009(%)
23
4.4
11.113.6 14.7
22.7
92.2
80.8
84.3
79.3
68.8
0
10
20
30
40
50
60
70
80
90
100
Minocycline TMP/SMZ Meropenem Ceftazidime Piperacillin/taz
R
S
Wang Fu, etal. CHINET 2009 surveillance of bacterial resistance in China. Chin J Infect Chemo 2010,10:325-334 24
0
10
20
30
40
50
60
20.5
36.4 37.6
41.3
36.3
4039
44.4
58.3 57.6
54.5 56
59.8
53
55.9
52.9
R S
Resistance and susceptibility rates in 12823 strains of
non-fermentative organisms(%),,,, 2009200920092009 ,,,,CHINETCHINETCHINETCHINET
Wang Fu, etal. CHINET 2009 surveillance of bacterial resistance in China. Chin J Infect Chemo 2010,10:325-334
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Antibiotics commonly used in the treatment ofP. aeruginosa infections
25Drug Resistance Updates (2000) 3, 247–255
26
Core antipseudomonalbeta beta-lactam antibiotics
Cefoperazone/sulbactam
Piperacillin/tazobactam Cefepime
Ceftazidime
Aztreonam
Imipenem
Meropenem
Doripenem
Selection of antibiotics
A therapeutic selection based on
The severity of the infection,
Awareness of underlying risk factors and co-morbid diseases,
Recognition of the epidemiology and resistancephenotypes in individual settings, and
Knowledge of pharmacokinetic–pharmacodynamicparameters
27
Monotherapy versus combination coverage
The potential clinical significance ofcombination therapy over monotherapy for P.aeruginosa pneumonia has been acontroversial subject for many years.
The use of combination therapy is thought to
minimize the emergence of resistance andto increase the likelihood of therapeuticsuccess through antimicrobial synergy
28
29
Pneumonia guidelines
2005 ATS/IDSA guidelines recommend
use of two anti-pseudomonaldrugs An antipseudomonal beta-lactam
PLUS
Either an aminoglycoside or a quinolone
Correlation Between AntibioticCorrelation Between AntibioticCorrelation Between AntibioticCorrelation Between AntibioticConsumption and Resistance inConsumption and Resistance inConsumption and Resistance inConsumption and Resistance in P. aeruginosa P. aeruginosa P. aeruginosa P. aeruginosa
Antibiotic class Hazard ratio
Ceftazidime 0.8
Piperacillin 5.2
Ciprofloxacin 9.2
Imipenem 44
Antimicrobial Agents Chemother. 1999;43:1379-1382
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31
Treatmwnt of P.aeroginosa resistant to
carbapenem
TherapeuticTherapeuticTherapeuticTherapeutic optionsoptionsoptionsoptions
Cefoperozone/sulbactamCefoperozone/sulbactamCefoperozone/sulbactamCefoperozone/sulbactam ((((checkcheckcheckchecksusceptibilitysusceptibilitysusceptibilitysusceptibility
ciprofloxacinciprofloxacinciprofloxacinciprofloxacin((((checkcheckcheckcheck susceptibilitysusceptibilitysusceptibilitysusceptibility))))
aminoglycosideaminoglycosideaminoglycosideaminoglycoside ((((checkcheckcheckcheck susceptibilitysusceptibilitysusceptibilitysusceptibility
colistncolistncolistncolistn
NoteNoteNoteNote
Many strains remain susceptible toMany strains remain susceptible toMany strains remain susceptible toMany strains remain susceptible toaztreonam, ceftazidime or AP Pensaztreonam, ceftazidime or AP Pensaztreonam, ceftazidime or AP Pensaztreonam, ceftazidime or AP Pens
Combination of (AP Pen & APAG) or (APCombination of (AP Pen & APAG) or (APCombination of (AP Pen & APAG) or (APCombination of (AP Pen & APAG) or (AP----3GC & APAG) may show in vitro activities3GC & APAG) may show in vitro activities3GC & APAG) may show in vitro activities3GC & APAG) may show in vitro activities
New antipseudomonalantibiotics
Doripenem
Biapenem Tomopenem
Ceftobiprole
Sitafloxacin
32Journal of Antimicrobial Chemotherapy (2009) 64, 229–238
Doripenem Doripenem is a new carbapenem with potent in vitro
activity against various aerobic and anaerobic Gram-positive
and Gram-negative bacteria.
In vitro antibacterial activity against wildtype P. aeruginosa
is 2–4 fold more potent than meropenem and imipenem
In a study comparing the in vitro activity of doripenem withother antipseudomonal antibiotics (imipenem, levofloxacin,
piperacillin, ceftazidime, aztreonam, tobramycin and
cefepime), the MIC of doripenem was lower than those of
all comparative agents against P. aeruginosa isolates
Doripenem had MIC90s of 2 and 16 mg/L for
ceftazidimesusceptible and -resistant isolates, respectively,
compared with meropenem (8 and 32 mg/L, respectively)and imipenem (16 and 32 mg/L, respectively)
33Journal of Antimicrobial Chemotherapy (2009) 64, 229–238
Doripenem
The first randomized, open-label, Phase III study72
of 531 patients compared doripenem 0.5 q8h with
imipenem 0.5 q6h
There was no statistically significant difference in
clinical cure between the two groups (68.3% for
doripenem and 64.8% for imipenem).
In a subgroup analysis, P. aeruginosa was isolated
from 28 patients in the doripenem group and 25 in
the imipenem group.
There was also a statistically non-significant trendtowards higher clinical cure rates with doripenem
[16/20 (80%)] versus imipenem [6/14 (42.9%)].
34Journal of Antimicrobial Chemotherapy (2009) 64, 229–238
Doripenem
A second randomized, Phase III, prospective, open-label study of 448 patients with nosocomial
pneumonia or early onset compared doripenem 0.5q8h with piperacillin/tazobactam 4.5 q6h.
Step-down therapy to oral levofloxacin wasallowed after 72 h.
Overall microbiological and the clinical cure rate inthe Clinical evaluated population were 84.5% and81.3% for doripenem and 80.7% and 79.8% forpiperacillin/tazobactam(p=NS) respectively.
35Journal of Antimicrobial Chemotherapy (2009) 64, 229–238
Biapenem
Biapenem is a parenteral carbapenem antibacterial
agent that was launched in Japan in 2002 and it is
currently in Phase II trials in the USA.
It has a broad spectrum of in vitro antibacterial
activity against Gram-negative (including b-
lactamase-producing strains and P. aeruginosa),
Gram-positive and anaerobic bacteria.
Biapenem shows a good post-antibiotic effect, similar
to imipenem, and has a high bactericidal activity
against Pseudomonas biofilm-forming strains and
several efflux system mutants.
36Journal of Antimicrobial Chemotherapy (2009) 64, 229–238
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Biapenem in vitro activity of biapenem against P. aeruginosa tends to
be similar to that of imipenem in most investigations
In clinical trials, 300 mg biapenem twice daily showed
clinical and bacteriological efficacy similar to that of 500mg imipenem twice in adult patients with various types of
bacteriologically documented lower respiratory tract
infections, including those with P. aeruginosa.
Clinical efficacy rates in the biapenem and imipenem
groups were 94.8% (73/77 patients) and 92.8% (64/69),
respectively.
Bacterial eradication was achieved in 90.9% (20/22) of
biapenem and 93.1% (27/29) of imipenem recipients.
37Journal of Antimicrobial Chemotherapy (2009) 64, 229–238
Tomopenem
a novel 1-b-methylcarbapenem that has avery broad-spectrum activity against Gram-
positive and Gram-negative bacteria,including P. aeruginosa, MRSA and PRSP.
In vitro and in vivo murine studies showedthat tomopenem exhibited improved activityagainst P. aeruginosa.
38Journal of Antimicrobial Chemotherapy (2009) 64, 229–238
Ceftobiprole
Ceftobiprole is a fifth-generation cephalosporinwith properties similar to those of tomopenem inits strong affinity for penicillin-binding proteins.
The antipseudomonal activity of ceftobiprole issimilar to that of cefepime, displaying identicalMIC50 and MIC90 in vitro studies.
In a study assessing 741 isolates of P. aeruginosa,72% of isolates were inhibited by 4 mg/Lceftobiprole, compared with 68% and 73% ofisolates being inhibited by 4 mg/L cefepime and
ceftazidime, respectively.
39Journal of Antimicrobial Chemotherapy (2009) 64, 229–238
Comparative in vitro activity vs P. aeruginosa (n=403)
Antimicrobial
agent
MIC50
(µµµµg/ml)
MIC90
(µµµµg/ml)
MIC Range
(µµµµg/ml)
Ceftobiprole 4 16 0.25->32
Ceftazidime 2 32 0.25->32
Cefepime 4 16 0.12–>32
Piperacillin-
Tazobactam
16 >128 0.5->128
Brown NP et al. Poster E-0112, presented at 46th ICAAC, Sept, 2006; San Francisco,
In vitro activity does not necessarily correlate with clinical results.
Ceftobiprole
Ceftobiprole has completed one Phase III
investigation for the treatment of hospital-acquired
pneumonia (HAP) including a subgroup of patientswith VAP.
Participants were randomized to receive 500 mg
ceftobiprole intravenously every 8 h as a 2 h infusion
or ceftazidime plus linezolid for a total of 7–14 days.
Seventy patients had P. aeruginosa pneumonia.
In the CE patient population excluding VAP, clinical
cure rates were 77% for ceftobiprole and 76% forcombination therapy
41Journal of Antimicrobial Chemotherapy (2009) 64, 229–238
Sitafloxacin
Sitafloxacin has activity comparable to that of
ciprofloxacin towards wild-type strains of P. aeruginosa,
but shows lower MICs for gyrA or parC mutants, due to abetter affinity for the mutated targets.
A Phase II, randomized, open-label, multicentre studydemonstrated that sitafloxacin (400 mg once daily) was
as safe and as well tolerated as imipenem (500 mg three
times a day) for the treatment of pneumonia, including
two cases of P. aeruginosa pneumonia, one in each group
42Journal of Antimicrobial Chemotherapy (2009) 64, 229–238
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Antimicrobial Agents for the Treatment of Acinetobacter Infections
43Clinical Infectious Diseases 2010; 51(1):79–84
44
The antibiotic armamentarium fortreatment of Acinetobacter
the most active agents are
Sulbactam containing regimen,
carbapenems,
colistin,
polymyxin
Carbapenem Use and MDRCarbapenem Use and MDRCarbapenem Use and MDRCarbapenem Use and MDR Acinetobacter Acinetobacter Acinetobacter Acinetobacter
Variable OR (95 % CI)
Age 1.03 (1.01-1.05)
Time at risk 1.02 (1.002 -1.03)
ICU stay 21.54 (10.73-43.23)
Imipenem 9.18 (3.99-21.13)
3-GC 2.11 (1.13-3.95)
Risk factors for imipenem –resistant A. baumannii
Antimicrob Agents Chemother. 2004;48:224- 228
Abx Associated with MDRAbx Associated with MDRAbx Associated with MDRAbx Associated with MDRA. baumannii and P. aeruginosaA. baumannii and P. aeruginosaA. baumannii and P. aeruginosaA. baumannii and P. aeruginosa
A.A.A.A. baumannii baumannii baumannii baumannii CarbapenemsCarbapenemsCarbapenemsCarbapenems
ThirdThirdThirdThird----generationgenerationgenerationgeneration
cephalosporinscephalosporinscephalosporinscephalosporins
P. aeruginosa P. aeruginosa P. aeruginosa P. aeruginosa CarbapenemsCarbapenemsCarbapenemsCarbapenems
FluorquinolonesFluorquinolonesFluorquinolonesFluorquinolones
Based on review of 55Based on review of 55Based on review of 55Based on review of 55 A.A.A.A. baumannii baumannii baumannii baumannii studies and 42studies and 42studies and 42studies and 42 P.P.P.P.aeruginosa aeruginosa aeruginosa aeruginosa studies that met prestudies that met prestudies that met prestudies that met pre----defined criteriadefined criteriadefined criteriadefined criteria
The multiThe multiThe multiThe multi----drug nature of efflux pump spectra means thatdrug nature of efflux pump spectra means thatdrug nature of efflux pump spectra means thatdrug nature of efflux pump spectra means that
virtually any antibiotic can select for resistance tovirtually any antibiotic can select for resistance tovirtually any antibiotic can select for resistance tovirtually any antibiotic can select for resistance toany otherany otherany otherany other
J. Hosp. Infect. 2006;64: 7-15.
Avoid using carbapenems if
possible…
- May decrease the frequency of imipenemresistance
- Decrease cost
The role of sulbactam
Sulbactam-containing regimen should be
considered as a therapeutic option formild to severe A. baumannii infectionscaused by sulbactam-susceptibleorganisms
48CLINICAL MICROBIOLOGY REVIEWS, July 2008, p. 538–582
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Acinetobacter spp . – Antimicrobial therapy
Acinetobacter spp . – Antimicrobial therapy
51
Treatment of Acinetobacter baumanni
resistant to carbapenem
Therapeutic options
Cefoperozone/sulbactam ,ampicillin/sulbactam (sulbactam alone is active againstsome A. baumanni)
colistn
Sulbactam: Two studies have shownsuperior outcome compared to colistin (J
Infect. 2008;56:432;J Antimicrob Chemother. 2008;61:1369)
We identified 22 microbiological studies reporting data for 2384 Acinetobacter spp. (1906 Acinetobacter baumannii).Susceptibility of atleast 90% of the Acinetobacter isolates to tigecycline (with an MIC
breakpoint of susceptibility 2 mg/L) was noted in 9/18 studies reportingdata on MDR Acinetobacter and in 7/15 studies reporting specific dataon carbapenem-resistant Acinetobacter.
The effectiveness of tigecycline for MDR Acinetobacter infections wasevaluated in eight identified clinical studies, reporting retrospective dataregarding 42 severely ill patients, among whom 31 had respiratory tractinfection (in 4 cases with secondary bacteraemia) and 4 hadbacteraemia.
Tigecycline therapy (in combination with other antibiotics in 28 patients)
was effective in 32/42 cases. In three cases, resistance to tigecycline developed during treatment.
52
53
CRAB的联合治疗的联合治疗的联合治疗的联合治疗
AAC, 2007,,,,51
舒普深舒普深舒普深舒普深3g,q8h,疗程疗程疗程疗程14天治疗鲍曼不动杆菌天治疗鲍曼不动杆菌天治疗鲍曼不动杆菌天治疗鲍曼不动杆菌HAP患患患患者者者者PK/PD参数与临床疗效关系的研究参数与临床疗效关系的研究参数与临床疗效关系的研究参数与临床疗效关系的研究((((n=12)
患者号患者号患者号患者号 MICs(µg/mL) %T>MIC 临床临床临床临床疗效疗效疗效疗效
细菌学细菌学细菌学细菌学疗效疗效疗效疗效
综合综合综合综合疗效疗效疗效疗效CPZ SUL CPZ SUL
10 1.5 0.75 304 128 治愈治愈治愈治愈 清除清除清除清除 治愈治愈治愈治愈
26 4 2 268 73 治愈治愈治愈治愈 清除清除清除清除 治愈治愈治愈治愈
14 16 8 211 60 治愈治愈治愈治愈 清除清除清除清除 治愈治愈治愈治愈
9 24 12 104 29 治愈治愈治愈治愈 清除清除清除清除 治愈治愈治愈治愈
8 4 2 123 60 治愈治愈治愈治愈 菌交替菌交替菌交替菌交替 治愈治愈治愈治愈
16 2 1 100 100 治愈治愈治愈治愈 菌交替菌交替菌交替菌交替 治愈治愈治愈治愈
18 16 8 68 0 治愈治愈治愈治愈 菌交替菌交替菌交替菌交替 治愈治愈治愈治愈
5 32 16 63 14 失败失败失败失败 未清除未清除未清除未清除 失败失败失败失败
13 48 24 44 10 失败失败失败失败 未清除未清除未清除未清除 失败失败失败失败
2 48 24 35 0 失败失败失败失败 未清除未清除未清除未清除 失败失败失败失败
7 48 24 30 0 失败失败失败失败 未清除未清除未清除未清除 失败失败失败失败
23 48 24 52 10 失败失败失败失败 未清除未清除未清除未清除 失败失败失败失败
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55
Treatment of S. maltophiliaTreatment of S. maltophiliaTreatment of S. maltophiliaTreatment of S. maltophilia RecommendedRecommendedRecommendedRecommended::::TMPTMPTMPTMP----SMZSMZSMZSMZ
AlternativeAlternativeAlternativeAlternative::::TC/CLTC/CLTC/CLTC/CL或或或或((((AztreonamAztreonamAztreonamAztreonam++++TCTCTCTC----CLCLCLCL))))
Minocyclin, doxycycline, ceftazidimeMinocyclin, doxycycline, ceftazidimeMinocyclin, doxycycline, ceftazidimeMinocyclin, doxycycline, ceftazidime
may also effectivemay also effectivemay also effectivemay also effective
Combination show in vitro synergyCombination show in vitro synergyCombination show in vitro synergyCombination show in vitro synergy
TC/CL+TMP/SMZ, TC/CL+CiprofloxacinTC/CL+TMP/SMZ, TC/CL+CiprofloxacinTC/CL+TMP/SMZ, TC/CL+CiprofloxacinTC/CL+TMP/SMZ, TC/CL+Ciprofloxacin
Data in mainland ChinaData in mainland ChinaData in mainland ChinaData in mainland China
Highly susceptible toHighly susceptible toHighly susceptible toHighly susceptible tocefoperazone/sulbactamcefoperazone/sulbactamcefoperazone/sulbactamcefoperazone/sulbactam
Sanford guideline 2010
Potency of tigecycline against non-fermentative Gram-negative bacteria
Organism MIC(mg/L) %S %R
Range MIC50 MIC90
P. aeruginosa (n = 1121) 0.12 to >32 8 16 5.1 77.2
Acinetobacter spp. (n = 326) 0.06-8 0.5 2 94.5 0.9
B. cepacia (n = 21) 0.25-32 1 16 67.0 29.0
S. maltophilia (n = 203) 0.12-8 1 2 93.1 3.0
56
Conclusion Pseudomonas aeruginosa, A. baumannii, S. maltophilia and
members of the B. cepacia complex are an increasingly
recognised cause of infection and are increasingly difficult
to treat.
There are currently no much more new drugs for the
treatment of multidrug resistant non-fermenters.
Therefore, currently available antibiotics require judicious
and prudent use, following evidence based trial data
whenever possible.
The role of combining these antibiotics in combating thedevelopment of further antibiotic resistance and delivering
superior clinical efficacy requires more rigorous evaluationthan in the past.
57Thank you for your attention ! Thank you for your attention ! Thank you for your attention ! Thank you for your attention !