Therapy Options for Acinetobacter infections
Transcript of Therapy Options for Acinetobacter infections
1
Therapy Options for Acinetobacter infections
viewed from the east
Minggui Wang, M.D.
Huashan Hospital, Fudan University
Shanghai, ChinaESCMID eLibrary
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OUTLINE
Three problems of Acinetobacter infections in clinical
Increasing trends of Acinetobacter infections
Highly resistant to antimicrobial agents of Acinetobacter
Emergence of hypervirulent Acinetobacter
Antimicrobial therapy of Acinetobacter infections
Controversies for combination or monotherapy?
Commonly used antimicrobials for combination therapies in
East
Cefoperozone-sulbactam, sulbactam, minocycline/doxycycline,
tigecycline, carbapenems, aminoglycosides, fosfomycin, rifampicin
2
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Gram-negative bacilli account for over 70% of all clinical isolates
in China
Gram-negative bacilli
70%
(62297/88778)
Gram-positive cocci
30%
(26481/88778)
CHINET 2015
67 68
66
70 71
72 72 72 73 73
70
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
Percentage of Gram-negative bacilli in total
clinical isolates (%)
CHINET national bacterial
resistance surveillance dataESCMID eLibrary
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44
Constituent ratio of A. baumannii, P. aeruginosa and K. pneumoniae
among all clinical isolates in China since 2005
9.28.7 8.8
10
1111.5 11.3
12.1 12
11.110.7
6
8
10
12
14
16 P. aeruginosa
A. baumannii
K. pneumoniae
CHINET national bacterial
resistance surveillance data
%
Hu FP, Clin Microbiol Infect 2016; 22: S9–S14
P. aeruginosa
K. pneumoniae
A. baumannii
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Antimicrobial resistance in Acinetobacter spp. in China (%)(n=9503, A. baumannii 93%)
0.2
9.7
38.142.8
45.849.1
58.7 60.8 6264.5 66.2 66.6 68.5 70.5
74.8
0
10
20
30
40
50
60
70
80
90
100
Poly
myx
in B
Tigec
yclin
e
Cefop
eraz
one/su
lbac
tam
Min
ocyc
line
Am
ikac
in
SXT
Getam
ycin
PIP/
TAZ
Imip
enem
Cipro
flox
acin
Cefop
ime
AM
P/SU
L
cefta
zidim
e
Mer
open
em
Pipe
racilli
n
Resistance rate(
%)
CHINET 2015
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Corelation of increasing trends of imipenem-resistance with
constituent ratio of A. baumannii clinical isolates in China since 2005
10
20
30
40
50
60
70
6
7
8
9
10
11
12
13
Ratio
%
Modified from Hu FP, Clin Microbiol Infect 2016; 22: S9–S14
Imipenem-resistance rate
Constituent ratio
CR
%
CHINET DATA
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77
Corelation of increasing trends of imipenem-resistance with
constituent ratio of K. pneumoniae clinical isolates in China since 2005
0
2
4
6
8
10
12
14
16
18
5
6
7
8
9
10
11
12
13
14
15
Ratio
%
Modified from Hu FP, Clin Microbiol Infect 2016; 22: S9–S14
Imipenem-resistance rate
Constituent ratio
CR
%
CHINET DATA
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Corelation of increasing trends of imipenem-resistance with
constituent ratio of P. aeruginosa clinical isolates in China since 2005
0
5
10
15
20
25
30
35
40
45
4
6
8
10
12
14
16
Ratio
%
Modified from Hu FP, Clin Microbiol Infect 2016; 22: S9–S14
Imipenem-resistance rate
Constituent ratio
CR
%
CHINET DATA
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A report of bacterial resistance in China 2005~2014
Antimicrobial resistance in five most common bacteria:
E. coli, K. pneumoniae, A. baumannii, P. aeruginosa and S. aureus
Hu FP, Clin Microbiol Infect 2016; 22: S9–S14
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1010
3.22.1 1.7 1.7 1.8 1.5 1.5 1.6 1.7
3
11
17
21 21
18 1820 20
0
5
10
15
20
25P.aeruginosa
A. baumannii%
CHINET DATA
Pan-drug resistance (PDR) in P. aeruginosa and A. baumannii
(colistin and tigecycline not included for AST)
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Emergence of hypervirulent and extensively drug resistant A. baumannii
A. baumannii is generally described as a low-virulence
organism, however it could be a highly virulent pathogen
A recent report from the US described that 6 patients with
relatively minor underlying disease were died from an
outbreak of XDR A. baumannii with hypervirulent.
11Jones CL, Clin Infect Dis 2015; 61:145-54
Paterson DL & Harris PNA. Clin Infect Dis 2015; 61:155-6
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Characteristics of the hypervirulent A. baumannii strains
Five clade B strains:
ST10, uncommon ST
type
Encoded 208 genes
homologous to
known virulence
factors
One clade A strain:
ST2, an international
clonal complexes
12
n=208
Jones CL, Clin Infect Dis 2015; 61:145-54
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OUTLINE
Three problems of Acinetobacter infections in clinical
Increasing trends of Acinetobacter infections
Highly resistant to antimicrobial agents of Acinetobacter
Emergence of hypervirulent Acinetobacter
Antimicrobial therapy of Acinetobacter infections
Controversies for combination or monotherapy?
Commonly used antimicrobials for combination therapies in
East
Cefoperozone-sulbactam, sulbactam, minocycline/doxycycline,
tigecycline, carbapenems, aminoglycosides, fosfomycin, rifampicin
13
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Antimicrobial therapy options for different resistance level A. baumannii infections
Nonmulti-resistant A. baumannii infection
First choice: β-lactam active following antibiogram results
Alternative: follow antibiogram results
Multiresistant A. baumannii infection
First choice: Carbapenem (if susceptible)
Alternative: Sulbactam
Carbapenem-resistant A. baumannii infection
First choice: Colistin
Consider addition of rifampicin in susceptible strains
Considered addition of aerosolized colistin in patients with
tracheobronchitis or ventilator-associated pneumonia
Alternative: Tigecycline
In complicated intra-abdominal and skin-structure infections, tigecycline
may be considered first-line agent especially in polymicrobial infections
Optimal dose in cases of pneumonia is unknown
Garnacho-Montero J & Amaya-Villar R. Curr Opin Infect Dis 2010; 23: 332
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Controversies on the combination therapy for XDR or PDR A. baumannii infections
Support
Necessary for
combination: Treatment
options are limited
Potential advantages of
combination: improved
efficacy due to synergy
Combination therapy is
commonly used in
clinical practice
15
Opposition
Lack of large randomized
clinical trial data (evidence-
based data)
Disadvantages of
combination
adverse events
potential drive towards
resistance
Paul M, J Antimicrob Chemother 2014; 69: 2305–9
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Polymyxin B in Combination vs alone in Critically Ill Patients
with A. baumannii or P. aeruginosa Infections
A retrospective cohort study in two ICUs from teaching hospitals in
Brazil
101pts: 33 (32.7%) were treated with polymyxin B in combination
and 68 (67.3%) with polymyxin B in monotherapy.
Results:
The overall 30-day mortality was 59.4% (60 pts), comprising 42.4% (14/33) and
67.6% (46/68) in combination and monotherapy groups, respectively (P=0.03).
The mortality rates were 18.5/1,000 patient days and 36.4/1,000 patient days in
the combination and monotherapy groups, respectively (P=0.02).
Combination therapy was independently associated with lower 30-day
mortality (P=0.001).
This is the first clinical study to show a benefit of combination over
monotherapy with polymyxin B for severe XDR A. baumannii or P.
aeruginosa infections
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Support of combination therapy
Rigatto MH, Antimicrob Agents Chemother 2015; 59: 6575–80
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Colistin versus Colistin plus Fosfomycin for Treatment
of Carbapenem-Resistant A. baumannii Infections
94 pts infected with CRAB were randomized to receive colistin
alone or colistin+fosfomycin (4g q12h ivgtt) for 7-14 d in Viet Nam
The pts who received combination therapy had a significantly more
favorable microbiological response
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Support of combination therapy
Sirijatuphat R, Thamlikitkul V, Antimicrob Agents Chemother 2014; 58: s598–s601
Combination Monotherapy P
Microbiological eradication (%)
End of study treatment100 81.2 0.01
Favorable clinical response (%)
End of study treatment 59.6 55.3 0.835
28-day all-cause mortality (%) 46.8 57.4 0.409
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Monotherapy versus combination therapy
for sepsis due to MDR A. baumannii
A prospective cohort study in 28 Spanish hospitals.
Monotherapy (MT): 68 (67.3%) pts; Combination therapy (CT) 33
(32.7%) . Pneumonia was the most common infection (50.5%)
The most common drugs used in MT: colistin (67.6%) and
carbapenems (14.7%); The most frequent combinations: colistin +
tigecycline (27.3%), carbapenem+ tigecycline (12.1%)
Results:
Crude 30 day mortality was 23.5% and 24.2% for the MT and CT groups
(P=0.94).
Multivariate analysis showed no trend towards reduced 30 day mortality with
CT (P=0.53)
Conclusions: The data do not support an association of CT with
reduced mortality in MDRAB infections.
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Opposition of combination therapy
Lopez-Cortes LE, J Antimicrob Chemother 2014; 69: 3119–26
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Colistin and Rifampicin Compared With Colistin Alone for the
Treatment of Serious Infections of XDR A. baumannii
This is a multicenter, randomized clinical trial in ICU of 5 tertiary
care hospitals in Italy
Conclusions:
In serious XDR A. baumannii infections, 30-day mortality is not reduced by
addition of rifampicin to colistin.
These results indicate that, at present, rifampicin should not be routinely
combined with colistin in clinical practice.
The increased rate of A. baumannii eradication with combination treatment
could still imply a clinical benefit.
19
Opposition of combination therapy
Durante-Mangoni E, Clin Infect Dis 2013; 57(3):349–58
Colistin + RFP (n=104)
Colistin (n=105)
P
28-day mortality (%) 43.3 42.9 0.95
A. baumannii eradication (%) 60.6 44.8 0.034
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Antimicrobial therapy of XDR A. baumannii in East
Extensively drug resistant (XDR) A.
baumannii is common, while polymyxins are
not available in some countries such as
China, so we are facing more difficult
situation for the treatment of A. baumannii
infections
Combination therapy is commonly used in
clinical practice
20
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Combination therapy for XDR A. baumanniiA Chinese consensus statement for XDR GNB infections
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Combinations based on sulbactam or its fixed-dose combination:
(cefoperazone-sulbactam or ampicillin-sulbactam) + tigecycline
(cefoperazone-sulbactam or ampicillin-sulbactam) + doxycycline
Sulbactam + carbapenems
Tigecycline-based combinations:
Tigecycline + (cefoperazone-sulbactam or ampicillin-sulbactam)
Tigecycline + carbapenems
Tigecycline + polymyxin
Polymyxin-based combinations:
Polymyxin + carbapenems
Polymyxin + tigecycline
Cefoperazone sulbactam + tigecycline +
carbapenems
Cefoperazone-sulbactam + doxycycline +
carbapenems
Imipenem + rifampicin + (polymyxin or
tobramycin)
Chinese XDR Consensus Working Group. Clin Microbiol Infect 2016; 22: S15–S25
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Commonly used antimicrobials for combination therapy for the treatment of
XDR A. baumannii in China
Cefoperazone-sulbactam and Sulbactam
Doxycycline/minocycline
Tigecycline
Carbapenems
Aminoglycosides
Rifampicin
fosfomycin
22
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Cefoperazone-sulbactam (CFP-SUL) and Sulbactam
Relatively low resistance rate of CFP-SUL in
A. baumannii
The resistance rate is lower than ampicillin-
sulbactam: 38% vs 67% in 2015
(unpublished CHINET data)
The antimicrobial susceptibility of CFP-SUL
is routinely tested for gram-negative bacilli
in China
CFP-SUL is available in several Asian
countries such as China, Japan, Korea,
Thailand and Phillipines. Sulbactam alone
available since 2014 in China
Breakpoints of CFP-SUL used:
S, ≤16/8 μg/ml; I, 32/16 μg/ml; R, ≥64/32
μg/ml (Jones RN, JCM 1987)
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CHINET national bacterial resistance
surveillance data
0
10
20
30
40
CFP-SUL resistance rate in A. baumannii
R%
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In-vitro Activity of Combination of CFP-SUL and Minocycline
against Carbapenem-Resistant A. baumannii
53 nonduplicate CRAB clinical isolates
Results:
Synergism 39 isolates
Partial synergism 11 isolates
Indifference 3 isolates
Conclusion: The combination of CFP-SUL with
minocycline had significant synergistic activity
against CRAB
24Pei G. Microb Drug Resist 2012; 18: 574-7
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In vitro activity of sulbactam in combination with imipenem,
meropenem, panipenem or cefoperazone against A. baumannii
Imipenem-susceptible
(n=40)(%)
Imipenem-resistant
(n=40)(%)
Synergy 20–27 7–25
Partial synergy 42–67 40–57
Additive 7–17 20–25
Indifference 0–12
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Conclusion:MICs of both the combined antimicrobials were reduced (FICI ≤1) in the majority of isolates, which could potentially improve the clinical outcomes of patients with intractable infections
Ji J. Int J Antimicrob Agents 2013; 41: 393– 401
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Molecular Mechanisms of Sulbactam Antibacterial
Activity and Resistance in A. baumannii
The antibacterial activities
of sulbactam are mediated
through inhibition of the
penicillin-binding proteins
(PBPs) PBP1 and PBP3
Resistance mechanisms
High level resistance: pbp3
mutations
Low level resistance: mutations
in the genes associated with cell
wall biosynthesis or stress
responses
26Penwell WF, Antimicrob Agents Chemother 2015; 59:1680–9
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Antimicrobial treatment of XDR A.
baumannii at a hospital in Shanghai
Antimicrobial therapy of 43 pts with XDR A. baumannii was
retrospectively analyzed
Conclusion: High-dose cefoperazone-sulbactam and carbapenem
alone or combined with other antibiotics could be considered
choices for treatment of XDR when other options are not available.
27Li Y, J Microbiol Immunol Infect 2015; 48, 101-8
Antimicrobials Efficacy rate %
Cefoperazone-sulbactam (n=8)Alone 4, with AMK/ISP 2, with
Dox/Mino 262.5
Carbapenem (n=19)Alone 12, with Dox/Mino 6, with
ISP 147.3
Cefoperazone-sulbactam+
carbapenem (n=7)Alone 4, with Dox/Mino 3 42.9
No antimicrobial treatment (n=7) 28.6
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A combination regimen for extensive burns with PDR
(colistin and tigecycline not tested) A. baumannii infection
9 cases with moderate or severe inhalation injuries
PDRAB infection first occurred in the respiratory system in all
nine patients. Wound infection in six patients (66.7%), and 4 of
those pts were blood cultures positive.
Antimicrobial dosage:
CFP-SUL 12 g/d (3.0 q8h)
Merpenem 6g/d
Minocycline 0.2 g/d PO
The treatment was effective in all nine patients, and bacterium
was eliminated in eight pts (89%)
28Ning F, Chin J Med 2014; 127(6):1177
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The use of Minocycline or Doxycyclinefor Acinetobacter infections
Minocycline is an “old drug” that was first introduced
in the 1960s.
It is approved for the treatment of A. baumannii
infections by FDA of the US.
In China, Minocycline is only available for oral
formulation, but has both oral and intravenous
preparations of Doxycycline.
Minocycline susceptibility is routinely tested for Acinetobacter
Intravenous doxycycline is used for XDR A. baumannii
infections.
Usually combined with CFP-SUL, carbapenems, or with both
of them
29Goff DA & Kaye KS. Clin Infect Dis 2014; 59: s365-6
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What is the difference of doxycyline and minocycline?
MIC50, µg/ml MIC90, µg/ml Susceptibility %
Minocycline 1 8 79
Doxycycline 2 >8 60
Imipenem >8 >8 37
Ampicillin-sulbactam >16/4 >16/4 26
30Castanheira M. Clin Infect Dis 2014; 59: s367-73
Doxycycline may have less central nervous adverse
effect of dizziness
A. baumannii clinical isolates are highly susceptible to
both of them
Minocycline has better activity (n=5478)
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3131
A. baumannii including XDR isolates have a relatively
high susceptible rate to minocycline in China
4
14
24
34
44
54
CHINET national bacterial
resistance surveillance data
R%
Hu FP, Clin Microbiol Infect 2016; 22: S9–S14
n
S, ≤4 µg/ml
MIC distribution of minocycline against
256 XDRAB
CARSS national bacterial resistance
surveillance data
Xu A, Clin Microbiol Infect 2016; 22: S1-8
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Doxycycline/Minocycline for MDR-AB infections
Ten retrospective studies regarding doxycycline
and minocycline for the treatment of 156 pts
with A. baumannii infections were reviewed
Combination therapy in 86% pts
Clinical success: 77% (120/156)
Respiratory infections: 72% (87/121)
Bloodstream infection: 87% (21/ 24)
Microbiological eradication: 71% (72/101)
32Falagas ME. Int J Antimicrob Agents 2015; 45: 455–460
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Tigecycline in combination for the treatment of Acinetobacter infections
Tigecycline+colistin
The most studied combination and showed promising efficacy
Tigecycline+cefoperazone-sulbactam
One of the commonly used combination regimens in China
Tigecycline was launched in China in 2011
Other combinations:
Tigecycline+carbapenems (meropenem, imipenem)
Tigecycline+sulbactam
Tigecycline+rifampin
33Cai Y, Infect Dis 2016; DOI: 10.3109/23744235.2016.1155735
Garnacho-Montero J, Expert Rev Anti Infect Ther 2015; 13:769–77
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Antimicrobial susceptibility in Acinetobacter in China
0.2
9.7
38.142.8
45.849.1
58.7 60.8 62 64.5 66.2 66.6 68.5 70.574.8
0
10
20
30
40
50
60
70
80
90
100
Polym
yxin B
Tigecyc
line
Cefpe
razo
ne/sulba
ctam
Minoc
yclin
e
Amikac
in
SXT
Getam
ycin
PIP/T
AZ
Imipen
em
Ciproflox
acin
Cefop
ime
AMP/SUL
ceftaz
idim
e
Merop
enem
Piperacillin
Resistance rate(
%)
CHINET 2015
Xu A, Clin Microbiol Infect 2016; 22: S1-8
MIC distribution of minocycline
against 256 XDRAB
CARSS national bacterial
resistance surveillance data
n
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In-vitro activity of Tigecycline and CFP-SULcombination against MDR A. baumannii
The combination
showed 29% of synergy
against 72 MDR strains
(all were CRAB)
Time-kill assays
confirmed the
synergistic interaction
in 3 of 4 XDR A.
baumannii
35Liu B, J Chemother 2015; 27: 271-6
Control1/2MIC TGC1/2MIC SCF
1 MIC TGC
1 MIC SCF
1/2 MIC combination1 MIC combinationESCMID eLibrary
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In-vitro activity of Tigecycline and CFP-SULcombination against MDR A. baumannii
The combination of tigecycline + CFP-SUL had better synergistic
effects than tigecycline+ SUL against XDR-AB
36Liu B, J Chemother 2015; 27: 271-6
Control1/2 MIC CFP1/2 MIC TGC + CFP
1/2 MIC TGC + SUL
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High dose tigecycline in critically ill pts withsevere infections of MDR bacteria
54 pts received a standard dose (SD) and 46 high dose (HD) of
TGC were enrolled in the ICU of a teaching hospital in Rome
SD: 50 mg q12h
HD: 100 mg q12h
CRAB (n=34) and CRKP (n =45) were the main isolated pathogens
Results:
In the VAP subgroup (63 pts: 30 received SD and 33 HD), the HD
group had a trends of better clinical and microbiological outcomes.
The only independent predictor of clinical cure was the use of high
tigecycline dose (P=0.009)
There were no pts requiring TGC discontinuation or dose reduction
because of adverse events, indicating the safety of higher dose
37De Pascale et al. Critical Care 2014, 18: R90
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SUMMARY
Acinetobacter has an increasing trends of isolation in clinical
specimens
Acinetobacter is highly resistant to antimicrobial agents and
hypervirulent Acinetobacter emerged
Antimicrobial therapy options for Acinetobacter
infections are rare
Although controversies exist, combination therapy is
commonly used in clinical practice
Commonly used antimicrobials for combination therapies in
China include:
Cefoperozone-sulbactam, Sulbactam, Minocycline/Doxycycline,
Tigecycline, Carbapenems, Aminoglycosides, Fosfomycin,
Rifampicin
38
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