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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3

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


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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66

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


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

%



Constituent ratio

CR

%

CHINET DATA

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88


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

%



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


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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?


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

16

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

17

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.

18

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

21

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)

23

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

25

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



R%


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


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

1/2 MIC TGC + CFP-SULESCMID eLibrary

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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


China include:

Cefoperozone-sulbactam, Sulbactam, Minocycline/Doxycycline,

Tigecycline, Carbapenems, Aminoglycosides, Fosfomycin,

Rifampicin

38

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Therapy Options for Acinetobacter infections

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