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Diagnostic Microbiology and Infectious Disease 70 (2011) 246 – 252

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Antimicrobial Susceptibility Studies

High mortality rates among solid organ transplant recipients infected with
extensively drug-resistant Acinetobacter baumannii: using in vitro
antibiotic combination testing to identify the combination of a carbapenem
and colistin as an effective treatment regimen☆,☆☆,★
Ryan K. Shieldsa,1 , Eun J. Kwaka,1 , Brian A. Potoskia , Yohei Doia , Jennifer M. Adams-Haducha ,
Fernanda P. Silvieraa , Yoshiya Toyodaa , Joseph M. Pilewskia , Maria Crespoa ,
A. William Pascullea , Cornelius J. Clancya,b,⁎, M. Hong Nguyena
a
University of Pittsburgh, Pittsburgh, Pennsylvania, USA
b
V.A. Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, USA
Received 18 June 2010; accepted 27 December 2010

Abstract

Extensively drug-resistant (XDR) Acinetobacter baumannii infections caused 91% (10/11) mortality in transplant recipients. Isolates were
colistin-susceptible initially, but susceptibility decreased during therapy in 40% (4/10). We tested antibiotic combinations against XDR
Acinetobacter in vitro and demonstrated positive interactions for carbapenem–colistin. Subsequently, 80% (4/5) of transplant patients
were treated successfully with carbepenem–colistin regimens.
Published by Elsevier Inc.

Keywords: Acinetobacter; Synergy; Colistin; Doripenem; Transplant

1. Introduction defined by resistance to more than 2 of the following

Acinetobacter baumannii has emerged as a major cause of
nosocomial infections. Indeed, A. baumannii has been
identified by the Infectious Diseases Society of America as
1 of the 6 particularly problematic pathogens (ESKAPE)
(Boucher et al., 2009). The organism is notable for its wide
range of resistance mechanisms (Mak et al., 2009).
Multidrug-resistant (MDR) A. baumannii is generally
☆
This work was completed at the University of Pittsburgh Medical
Center, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
☆☆
Financial Support. The study was funded by the University of
Pittsburgh School of Pharmacy and by seed support from the University of
Pittsburgh, Department of Medicine to the Transplant Infectious Diseases
Program (MHN and CJC).
★
Potential Conflicts of Interest. RKS, YD, EJK, BAP, JMA, FS, YT,
JMP, MC, CJC and MHN: no conflict.
⁎ Corresponding author. Tel.: +1-412-383-5193; fax: +1-412-648-6399.
E-mail address: cjc76@pitt.edu (C.J. Clancy).
1
These authors contributed equally to this study.
0732-8893/$ – see front matter. Published by Elsevier Inc.
doi:10.1016/j.diagmicrobio.2010.12.023
broad-spectrum antimicrobial classes: antipseudomonal
cephalosporins, antipseudomonal carbapenems, ampicillin–
sulbactam, fluoroquinolones, and aminoglycosides (Adams-
Haduch et al., 2008). Increased use of broad-spectrum
antibiotics has induced the development of extensively drug-
resistant (XDR) isolates, defined by resistance to all agents
with the exception of tigecycline and polymyxins (colistin)
(Souli et al., 2008).
The treatment of XDR A. baumannii infections is
challenging because of the lack of treatment options and
management experience. Previously, the case of a lung
transplant recipient who developed pneumonia due to XDR
A. baumannii was reported from our institution (Doi, Husain,
Potoski et al., 2009). The patient was treated with colistin
plus tigecycline, but failed to clear the infection and died. We
continued to encounter serious XDR A. baumannii infections
among our solid organ transplant (SOT) recipients. In
general, our therapeutic strategies consisted of various
combinations of antimicrobials that have included colistin
 R.K. Shields et al. / Diagnostic Microbiology and Infectious Disease 70 (2011) 246–252
and/or tigecycline. Despite reports of successful therapy
using these regimens (Schafer et al., 2007), our experience
was dismal. In response, our Antibiotic Management and
Transplant Infectious Diseases (AMP and TID) programs
partnered to devise an institution-specific treatment regimen
for XDR A. baumannii infections. We used a variety of
methods to test our XDR A. baumannii isolates for in vitro
susceptibility to multiple antimicrobial combinations. On the
basis of these results, we recommended that the combination
of a carbapenem and colistin be adopted as standard therapy
for XDR A. baumannii infections among our SOT patients.
In this paper, we review our clinical experience before
devising the carbapenem–colistin regimen, describe the
results of in vitro testing, and report on our early experience
using the carbapenem–colistin regimen to treat SOT
recipients with XDR A. baumannii infections.
2. Methods
2.1. Bacterial strains
XDR A. baumannii isolates were obtained from the
clinical microbiology laboratory at the University of
Pittsburgh Medical Center (UPMC). Isolates were stored at
−80 °C and subcultured a minimum of 3 times before
experimentation. MICs were repeated for all agents by E-test
(AB bioMérieux, Solna, Sweden).
2.2. Synergy testing
All the experiments below were performed at least in
duplicate. Pseudomonas aeruginosa ATCC 27853 and
Escherichia coli ATCC 25922 were used as controls for
each set of experiments.
2.3. E-test
Three hundred microliters of a suspension equivalent to
the 0.5 McFarland turbidity standard was streaked onto
150-mm Mueller–Hinton II plates. After drying for 30 min
at 35 °C, an E-test for drug A was placed onto the agar for
1 h at 35 °C and then removed. Next, an E-test for drug B
was placed over the demarcation left from drug A. The
resulting combination MIC was read between 18–24 h of
incubation at 35 °C (Haddad et al., 2005).
2.4. Checkerboard microdilution
Checkerboard microdilution (CBM) synergy testing was
performed on XDR A. baumannii isolates (Pillai, Moelle-
ring Jr, and Eliopoulos, 2005). The fractional inhibitory
concentration index (∑FIC) was used to interpret the
results of CBM synergy after 24 h of incubation at 35 °C
(Pillai et al., 2005).
2.5. Time-kill assay
Time-kill assay (TKA) experiments were performed
using a starting concentration of 1 × 106 CFU/mL according
247
to published guidelines (National Committee for Clinical
Laboratory Standards, 1999). Concentrations in TKA were
selected based on the combination MICs identified by CBM.
Colony counts for all isolates were determined at 0, 2, 4, 8,
12, and 24 h. The results were presented as the mean of all
experiments for each isolate.
2.6. Patient population and definitions
All SOT patients with infection due to XDR A. baumannii
at the UPMC between November 2006 and August 2009
were included in the analysis. This study was approved by
the institutional review board at the University of Pittsburgh.
All patients were evaluated and managed by our TID service
as part of routine patient care. The classifications of
colonization versus disease due to XDR A. baumannii and
the outcome were made by the treating TID physicians and
independently confirmed by at least 2 investigators. The
primary outcome in this analysis was clinical success at
28 days (from the time of first positive cultures), and the
secondary outcome was death from any cause at 90 days.
3. Results
Between November 2006 and December 2009, we
encountered 11 SOT recipients with diseases caused by
XDR A. baumannii (Table 1). All isolates tested exhibited
colistin MICs ≤ 2 μg/mL, while the 7 isolates tested for
susceptibility to tigecycline exhibited MICs ≥2 μg/mL.
Patient outcomes were dismal despite treatment with regi-
mens previously published to be effective (Motaouakkil
et al., 2006; Schafer et al., 2007) (Table 1): the rates of
clinical success and survival at 28 and 90 days, respec-
tively, were 9% (1/11). In addition, serial isolates recovered
from 40% (4/10) of patients treated with colistin demon-
strated increasing MICs. Three of these patients had
persistent disease, while the fourth had recurrent infection
with XDR A. baumannii. In the 3 patients with persistent
disease (patients 4, 8, and 10; Table 1), colistin MICs
increased from 0.5 to N256 μg/mL within 55 days, ≤0.125
to N64 μg/mL within 19 days, and 0.5 to 2 μg/mL within
6 days, respectively.
Given this experience, our AMP and TID services
partnered to devise an institution-specific treatment strategy.
We first tested 17 XDR A. baumannii isolates from unique
patients and confirmed that they acquired the OXA-23 gene
(Adams-Haduch et al., 2008). We determined in vitro
susceptibility to various antibiotics, alone and in combina-
tion, using an E-test methodology (Table 2). Positive
interactions (defined as synergy or additivism) were
observed most commonly for the combination of colistin
or ampicillin/sulbactam with a carbapenem. The combina-
tion of colistin with doripenem was considered to be most
attractive because colistin was active as a single agent and
doripenem is our formulary preferred carbapenem. We
confirmed the positive interactions between these agents by
 248
Table 1
Demographics and case summaries of 11 SOT recipients (preintervention) and 5 SOT recipients (postintervention) with diseases caused by XDR A. baumannii
Patient Age/sex (diseasea) Transplant type APACHE II Disease (onset MIC (μg/mL) Additional agent(s) Clinical responsec Mortality (follow-up)

R.K. Shields et al. / Diagnostic Microbiology and Infectious Disease 70 (2011) 246–252
after transplant) (durationb)
Treatment regimen: colistin and ampicillin/sulbactam
1 36/woman (NASH) Liver 20 VAP (19 days) COL: 2 None (15 days) Successd Alive (11 months)
TGC: NP
2 80/man (ischemic cardiomyopathy) Heart 25 VAP (before transplant) COL: 0.25 None (3 days)e Failure Death
TGC: NP
3 63/man (ulcerative colitis) Liver 16 VAP and Bacteremia (55 days) COL: NP None (9 days)e Failure Death
TGC: NP
Treatment regimen: colistin and tigecycline
4 55/woman (Sjogren syndrome) Double Lung 20 VAP (85 days) COL(1): 0.5 INH colistin (38 days) Failure Death
COL(2)f: N256
TGC: 3
5 47/woman (pulmonary fibrosis) Single Lung 28 VAP and Mediastinitis (5 days) COL: ≤ 0.125 INH colistin (17 days) Failure Death
TGC: 6
6 43/man (obliterative bronchiolitis) Double Lung First episode VAP (24 days) COL: ≤ 0.125 INH colistin rifampin (52 days) Recurrence Death
8 TGC: 2
Second episode VAP (47 days) COL: 32 INH colistin Failure
14 TGC: 2 Amp-sulbactam
rifampin
(41 days)e
7 58/man (ischemic cardiomyopathy) Heart 17 VAP (29 days) COL: 2 INH colistin Failure Death
TGC: 6 rifampin (8 days)e
8 63/man (ischemic cardiomyopathy) Heart 28 Mediastinitis, VAP and COL(1): ≤ 0.125 Amikacin (17 days)e Failure Death
Empyema (11 days) COL(2)g: 64
TGC: 3
Treatment regimen: colistin and rifampin
9 68/woman (IPF) Double Lung 17 VAP (12 days) COL: 0.25 None (6 days)e Failure Death
TGC: NP
10 65/man (polycystic renal disease) Kidney 24 VAP and Bacteremia (18 years) COL(1): 0.5 None (30 days) Failure Death
COL (2)h: 2
TGC: 6
Treatment regimen: tigecycline and cefepime
11 58/man (cryptogenic cirrhosis) Liver 27 VAP and Bacteremia (81 days) COL: 0.25 None (6 days)e Failure Death
TGC: 3
Treatment regimen: carbapenem and colistin (postintervention)
1 67/woman (COPD) Double Lung 19 VAP and Empyema (23 days) COL: ≤ 0.125 Doripenem 500mg TID Failure Death
TGC: NP INH colistin (24 days)e
2 53/man (interstitial nephritis) Kidney 18 VAP (2.5 years) COL: NP Doripenem 250 mg BIDi Success Alive (5 months)
TGC: NP ampicillin–sulbactam (30 days)
 R.K. Shields et al. / Diagnostic Microbiology and Infectious Disease 70 (2011) 246–252 249

COL = colistin; TGC = tigecycline; NP = not performed; NASH = nonalcoholic steatohepatitis; IPF = idiopathic pulmonary fibrosis; INH = inhaled; COPD = chronic obstructive pulmonary disorder; VAP =
microtiter checkerboard method (data not shown). We then
Alive (7 months)

Alive (4 months)
further characterized 5 isolates using TKAs. For all 5,
Alive (1 year)

doripenem alone at concentrations ≤ MIC exerted no

activity, as kill curves were similar to control isolates
grown in the absence of drug. Colistin at concentrations
ranging from 0.25 to 1× MIC, on the other hand, was

Clinical response was assessed at 28 days from the time of first positive culture by the treating Transplant Infectious Diseases physician and confirmed by at least 2 investigators.
bacteriostatic against all isolates, inhibiting growth of the
inocula, but not causing significant kills. Combinations of
doripenem at concentrations achievable in serum and colistin
Success

Success

Success

at 0.125 to 0.25× MIC, however, resulted in complete kills

by 8 h without evidence of regrowth by 24 h (Fig. 1).
Based on the in vitro data, we recommended the
combination of doripenem 500 mg every 8 h (given over a
Meropenem 500 mg QDj

4-h infusion if possible) and colistin 5 mg/kg per day

Doripenem 500 mg TIDi
Doripenem 500 mg TID
INH colistin (28 days)

INH colistin (46 days)

INH colistin (44 days)

(divided in 2–4 doses) as the regimen of choice for the

treatment of OXA-23–producing XDR A. baumannii
Meropenem was used instead of doripenem because the patient was on hemodialysis, and the dosage of doripenem in this setting is not known.

infections among SOT recipients. Doses of doripenem

and colistin were adjusted according to the patient's renal
function. We also recommended inhaled colistin (150 mg
twice a day) be added to the parenteral regimen for
patients with pneumonia (Korbila et al., 2009). To date, 4
patients have been treated with this combination, and a
COL: 0.25

fifth patient received meropenem plus colistin (Table 1,

TGC: NP

TGC: NP
COL: 0.5
COL: 2

TGC: 2

Fig. 2). Eighty percent (4/5) of SOT recipients treated with

a carbapenem and colistin had a positive clinical response
and 80% (4/5) survived.

4. Discussion
VAP (3.5 years)

VAP (187 days)

VAP (17 days)

Our pilot study on XDR A. baumannii is important for

Treated with ampicillin/sulbactam 3 g IV every 6 h and colistin 180 mg IV every 12 h.

several reasons. We showed that a systematic approach of

identifying the mechanism of carbapenem resistance
combined with knowledge of optimal antimicrobial combi-
nation therapy based on in vitro susceptibility testing and
TKA enabled us to devise an effective therapeutic option
for XDR A. baumannii infections. Although several earlier
studies showed in vitro synergy between carbapenems and
15

15

25

polymyxins against XDR A. baumannii isolates (Pankey

Doripenem added after 14 days of colistin monotherapy.

and Ashcraft, 2009; Sopirala et al., 2010; Urban et al.,

Small Bowel

Single Lung

Single Lung

2010), to our knowledge, this study is the first to assess the

efficacy of a carbapenem and colistin combination in the
treatment of patients with XDR A. baumannii infections.
Underlying disease before transplantation.

Our report offers new insight into the treatment of XDR A.

Total duration of antimicrobial therapy.

Isolated 19 days after the first isolate.

Isolated 55 days after the first isolate.

baumannii that may be relevant to other centers and patient

Isolated 6 days after the first isolate.
44/woman (short-gut syndrome)

populations.
Treatment continued until death.

Emerging evidence suggests that A. baumannii exhibits

ventilator-associated pneumonia.

geographic specificity, as reports have demonstrated genetic

relatedness of isolates within individual medical centers and
56/woman (IPF)

66/woman (IPF)

different regions of the United States (Landman et al., 2009).

As such, it is plausible that antimicrobial susceptibility
patterns and the underlying resistance mechanisms among
isolates within an institution may not be applicable to other
locations. For example, OXA-23 production has been shown
to be the major mechanism of carbapenem-resistant
b

g
h
a

e
f

i
j

A. baumannii at our medical center (Adams-Haduch et al.,

3

5
250 R.K. Shields et al. / Diagnostic Microbiology and Infectious Disease 70 (2011) 246–252

Table 2
In vitro synergy testing against XDR A. baumannii by E-test methodology
Backbone agent Agents tested in combination Synergy no. (%) Additivism no. (%) Indifference no. (%) Antagonism no. (%)
Ampicillin/sulbactam Colistin 0 (0) 2 (12) 13 (76) 2 (12)
Doripenem 0 (0) 7 (41) 10 (59) 0 (0)
Imipenem 0 (0) 8 (47) 9 (53) 0 (0)
Rifampin 1 (6) 5 (29) 11 (65) 0 (0)
Tigecycline 1 (6) 1 (6) 15 (88) 0 (0)
Colistin Doripenem 0 (0) 5 (29) 12 (71) 0 (0)
Imipenem 0 (0) 6 (35) 11 (65) 0 (0)
Rifampin 0 (0) 1 (6) 15 (88) 1 (6)
Tigecycline 0 (0) 1 (6) 15 (88) 1 (6)
Rifampin Doripenem 2 (12) 2 (12) 13 (76) 0 (0)
Imipenem 2 (12) 1 (6) 14 (82) 0 (0)
Tigecycline 0 (0) 4 (24) 13 (76) 0 (0)
Interaction between 2 drugs were determined according to:
P
= FIC = MIC MIC
of drug A in combination
of drug A alone + MIC MIC
of drug B in combination
of drug B alone .
Synergy is defined as ΣFIC ≤0.5; additivism, ΣFIC N0.5–1.0; indifference, ΣFIC N1.0–4.0; antagonism, ΣFIC N 4.0.

2008), whereas OXA-40 carbapenemase, reduced expres-
sion of outer membrane proteins, and the overexpression of
efflux pumps were the mechanisms of resistance during
several other A. baumannii outbreaks in the United States
(Lee et al., 2010; Lolans et al., 2006; Perez et al., 2007).
Although we demonstrated that the isolates in this study
contained OXA-23, we cannot exclude that other mecha-
nisms contributing to resistance also may have been present.
Discrepancies in resistance mechanisms between isolates
from different centers may explain, at least in part, why
combination regimens reported as successful in the literature
were not successful among our patients. Perhaps the most
popularly cited combination for treatment of XDR
A. baumannii is colistin and rifampin, which has been
supported by both in vitro (Giamarellos-Bourboulis et al.,
Fig. 1. Representative TKA against an XDR A. baumannii isolate.
2001) and in vivo data (Motaouakkil et al., 2006; Song et al.,
2008). In our experience, however, colistin and rifampin
were antagonistic or indifferent for 6% (1/17) and 88%
(15/17) of isolates, respectively. Moreover, both patients
who were treated with this combination died during their
hospitalizations. Our results should encourage other institu-
tions to conduct independent investigations to identify the
predominant strain(s) of A. baumannii locally, their
mechanisms of resistance, and the optimal antimicrobial
combinations against XDR isolates.
This study is also notable for the insights it affords
into colistin resistance. Before the introduction of the
carbapenem–colistin combination, colistin resistance deve-
loped in 4 SOT recipients treated with colistin-containing
regimens. Colistin is used increasingly for the treatment of
A. baumannii and other resistant Gram-negative infections,
both alone and in antimicrobial combinations. Increased
use of colistin, however, has raised concerns about the
emergence of resistance (Hawley et al., 2008), and our
clinical experience suggests that such concerns are
justified. This phenomenon underscores the importance of
preserving colistin susceptibility by using optimal antimi-
crobial combinations. Effective combination therapy with
colistin, therefore, may serve the dual purpose of decreasing
MICs to levels conducive to more favorable therapeutic
responses and playing a role in preventing the emergence
of resistance.
The extremely high rate of tigecycline nonsusceptibility
among XDR A. baumannii isolates from our institution
exceeds that of previous reports. In the absence of molecular
typing, we cannot exclude that at least some of our isolates
were clonal (Adams-Haduch et al., 2008). Nevertheless, our
experience differs from certain geographic regions, in which
tigecycline susceptibility rates among MDR and XDR
A. baumannii isolates remain high (Gales et al., 2006). At
present, the clinical efficacy of this agent against MDR and
XDR A. baumannii is undefined, the emergence of
tigecycline resistance has been reported (Savini et al.,
 R.K. Shields et al. / Diagnostic Microbiology and Infectious Disease 70 (2011) 246–252 251

Combination
Therapy

Pre-intervention Post-intervention
(n = 11) (n = 5)

Colistin-based Tigecycline + Colistin+

therapy (n = 10) Cefepime (n = 1) Carbapenem
(n = 5)

Colistin + Colistin + Clinical success

Tigecycline Colistin+ Inhaled Colistin Ampicillin/
Ampicillin/ (0%) (n = 4) sulbactam (n = 1)
sulbactam (n = 3) (n = 5) Rifampin (n = 2) Survival (0%)

Clinical success Clinical success Clinical success Clinical success

(33%) Inhaled Colistin Amikacin (0%)
(n = 4) (n = 1) (75%) (100%)
Survival (33%) Survival (0%) Survival (50%) Survival (100%)

Clinical success Rifampin Clinical success

(0%) (n = 2) (0%)
Survival (0%) Survival (0%)

Clinical success
(0%)
Survival (0%)

Fig. 2. Clinical outcomes and mortality for 16 SOT patients with diseases caused by XDR A. baumannii.

2008), and treatment failures are well recognized (Peleg Acknowledgments

et al., 2007). Moreover, poorer outcome was observed
among patients with ventilator-associated pneumonia treated
with tigecycline in a recent study (Freire et al., 2010).
Therefore, we suggest that patterns of in vitro susceptibility
to tigecycline should be established at individual institutions
before using the agent; furthermore, tigecycline should be
used cautiously for treating ventilator-associated pneumonia.
It is important to acknowledge that the small size of our
study limits the ability to draw definitive conclusions about
the role of carbapenem–colistin combination therapy for
XDR A. baumannii infections. Although we have used
doripenem as the preferred carbapenem at our institution, our
in vitro data suggest that other anti-pseudomonal carbape-
nems may be equally efficacious. Since A. baumannii
infections are often recurrent, it is also important to follow
patients with XDR A. baumannii infections for several
months to determine the durability of clinical responses. In
vitro susceptibility to colistin and, in particular, tigecycline
should not be presumed, but rather established by clinical
microbiology laboratories for each isolate of XDR A.
baumannii. The role of routine synergy testing is still not
clear and remains both labor- and cost-intensive (Aaron,
2007). Of note, a randomized clinical trial comparing colistin
monotherapy versus imipenem–colistin combination thera-
py against MDR Acinetobacter has been recently funded by
the US National Institutes of Health, which may provide
future guidance (Paterson and Rogers, 2010). Given the
limited therapeutic options against XDR A. baumannii,
clinicians are encouraged to identify novel treatment
combinations that may be useful at their centers.
Experiments were conducted in the laboratories of Drs.
Nguyen and Clancy at the University of Pittsburgh. The
authors would like to thank Randy Smith, Senior Associate
Dean of the School of Pharmacy, the University of
Pittsburgh School of Pharmacy, and the University of
Pittsburgh Department of Medicine for their generous
financial support. We are also indebted to Kelley Wasicek
and the Department of Pharmacy at the University of
Pittsburgh for assistance in completing this study. Finally,
we would like to extend our gratitude to Lloyd Clarke for his
assistance with data collection and interpretation.
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