INVITED ARTICLE REVIEWS OF ANTI-INFECTIVE AGENTS

Louis D. Saravolatz, Section Editor

Treatment of Acinetobacter Infections

Joel Fishbain1 and Anton Y. Peleg2,3,4
1
Division of Infectious Diseases, St John Hospital and Medical Center, Detroit, Michigan, and 2Division of Infectious Diseases, Massachusetts General Hospital
and Beth Israel Deaconess Medical Center, Boston, Massachusetts; 3Alfred Hospital and 4Department of Microbiology, Monash University, Melbourne, Australia

Acinetobacter baumannii remains an important and difficult-to-treat pathogen whose resistance patterns result in significant
challenges for the clinician. Despite the prevalence and interest in A. baumannii infections, there is relatively limited well-
controlled scientific data to help the clinician select optimal empirical and subsequent targeted therapy for a variety of
infections. We will review the currently available antimicrobial agents and discuss the clinical data supporting the use of the
various agents.

INTRODUCTION
The challenges of treating multidrug-resistant bacteria continue
to be at the forefront of the clinician’s practice in caring for
hospitalized patients. Acinetobacter baumannii has proven to be
an increasingly important and demanding species in health care–
associated infections. The drug-resistant nature of the pathogen
and its unusual and unpredictable susceptibility patterns make
empirical and therapeutic decisions even more difficult.
The association of A. baumannii with pneumonia, bactere-
mia, wound infections, urinary tract infections, and meningitis
has been well described [1]. Risk factors associated with col-
onization or infection (which can be difficult to distinguish)
include prolonged hospitalization, intensive care unit admis-
sion, recent surgical procedures, antimicrobial agent exposure,
central venous catheter use, prior hospitalization, nursing home
residence, and local colonization pressure on susceptible pa-
tients [1–3].
The ability of A. baumannii to survive for extended periods
on environmental surfaces is notorious and is likely important
for transmission within the health care setting. Multidrug re-
sistance is common with health care–associated A. baumannii
infections. The impressive number of acquired mechanisms of
resistance makes selection of an appropriate empirical anti-
microbial agent exceedingly difficult. The diversity of resistance
Received 13 January 2010; accepted 9 March 2010; electronically published 26 May 2010.
Reprints or correspondence: Dr Joel Fishbain, Div of Infectious Diseases, St John Hospital
and Medical Ctr, 19251 Mack Ave, Ste 333, Grosse Pointe Woods, Michigan 48236 (Joel
.Fishbain@stjohn.org).
Clinical Infectious Diseases 2010; 51(1):79–84
 2010 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2010/5101-0013$15.00
DOI: 10.1086/653120
mechanisms is beyond the scope of this article but can be re-
viewed in Peleg et al [4]. Degradation enzymes against b-lac-
tams, modification enzymes against aminoglycosides, altered
binding sites for quinolones, and a variety of efflux mecha-
nisms and changes in outer membrane proteins have been re-
ported. Essentially, any and all of these elements can be com-
bined to result in a highly drug-resistant, and at times pan-
resistant, opportunistic pathogen [4].
Attributable mortality has been difficult to assess for an or-
ganism that appears to be as much a colonizer as it is a true
pathogen. Although one cannot argue against the pathogenic-
ity of an organism that is identified in bloodstream infections,
A. baumannii is often identified in the sputum samples of pa-
tients with mechanical ventilation. This quandary of patho-
genicity has added to the difficulty of treating these highly
resistant organisms, because many therapeutic strategies are
associated with significant toxicity. The in-hospital attributable
mortality appears to be 8%–23%, but for the intensive care
unit, it was found to be 10%–43% [5, 6]. Although most stud-
ies did not demonstrate a statistically significant difference be-
tween case patients and control subjects, all studies did show
a higher mortality among the case patients. Despite the lack of
consistent statistical support for the findings, one has to assume
that A. baumannii is at least as important as other pathogens
isolated from patients. The decision to treat on the basis of a
clinical culture result remains in the hands of the clinician, and
criteria for decision-making in this regard will not be reviewed
in this article. We will endeavor to discuss the therapeutic op-
tions using available clinical data (Table 1). The reader is en-
couraged to review the in vitro and animal studies for addi-
tional information.

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 Table 1. Antimicrobial Agents for the Treatment of Acinetobacter Infections

a
Medication Dosage Route Toxicity Comments

Sulbactam (amp/sulb in 6 g per day IV Dermatologic, GI, nephritis Adjust for renal function; daily dose based
the United States) on sulbactam
Imipenem-cilastatin 500 mg every 6 h up to 1 g IV Phlebitis, GI, anaphylaxis, seizures, Extended infusions have been used, lim-
every 6–8 h nephritis ited data
Meropenem 500 mg to 1 g every 8 h IV GI, headache, dermatologic, hemato- Extended infusions have been used, lim-
logic, angioedema, seizure ited data
Doripenem 500 mg every 8 h IV Dermatologic, GI, anemia, anaphy- Consider extended infusion
laxis, seizure
Amikacin
Regimen 1 15 mg/kg daily IV Nephrotoxicity, ototoxicity, neuromus-
cular blockade
Regimen 2 30 mg IVent
Tobramycin
Regimen 1 4–7 mg/kg daily IV Nephrotoxicity, ototoxicity, neuromus- Peak and trough measurements as appro-
cular blockade priate for dosing regimen selected
Regimen 2 300 mg (1 ampule) twice daily IH Tobi inhaled formulation
Regimen 3 5– 20 mg IT/IVent Not for children Not FDA approved for this route of
administration
Colistin (colistimethate)
Regimen 1 5 mg/kg/day, 2–4 divided IV Nephrotoxicity and neurotoxicity Additional data still required on ideal
doses dosing
Regimen 2 1–3 million IU every 8 h IH Must be used immediately after re- 1 million IU is 80 mg of colistimethate. A
constitution to prevent accumula- variety of doses used in studies
tion of colistin–lung toxicity
Polymyxin B [25] 50,000 units daily (5 mg IT Meningeal irritation Has been used as intraventricular injec-
tion but not FDA labeled as approved
by this route
Polymyxin E (colistin [25]) 10 mg daily IT/IVent Meningeal irritation Has not been FDA approved for either
route of administration
Tigecycline 100 mg once then 50 mg ev- IV GI, shock, pancreatitis, anaphylaxis Avoid use in blood stream infections due
ery 12 h to large volume of distribution and low
mean maximum. steady-state levels
Minocycline 100 mg every 12 h IV GI, hepatic, dermatologic MIC90 lower than that of doxycycline; lim-
ited data on use in severe infections;
most active of all the tetracyclines [33]
(excluding tigecycline because of lack
of established breakpoints)

NOTE. Amp/sulb, ampicillin-sulbactam; FDA, US Food and Drug Administration; GI, gastrointestinal (eg, nausea, vomiting, and diarrhea); H, inhalational;
hepatic, jaundice and hepatitis; IT, intrathecal; IV, intravenous; IVent, intraventricular.
a
Based on adults with normal renal function.

SPECIFIC THERAPEUTIC OPTIONS
Sulbactam. Of the b-lactamase inhibitors, sulbactam pos-
sesses the greatest intrinsic bactericidal activity against A. bau-
mannii isolates [4]. Results of clinical investigations have doc-
umented the efficacy of sulbactam (commercially available in
the United States in combination with ampicillin) in mild-to-
severe A. baumannii infections. Urban et al [7] have reported
one of the earliest experiences using ampicillin-sulbactam and
observed that 9 of 10 patients who were seriously ill and re-
ceiving mechanical ventilation demonstrated clinical improve-
ment using ampicillin-sulbactam at a dosage of 3 g of amicillin
and 1.5 g of sulbactam intravenously every 6 or 8 h. Sulbactam-
containing regimens appeared to be comparable to regimens
of other agents when the infecting organisms were susceptible
to sulbactam in patients with A. baumannii pneumonia and
blood stream infections [8–10]. A study from Israel identified
that treatment with ampicillin-sulbactam was the only statis-
tically significant variable associated with reduced mortality in
patients with multidrug-resistant A. baumannii bloodstream
infection [11]. Mixed results have been reported for use of
sulbactam to treat A. baumannii meningitis, and this likely
relates to impaired drug penetration. The optimal dosage of
sulbactam to treat serious A. baumannii infections is unknown,
but most authors recommend at least 6 g per day in divided
doses for patients with normal renal function (Table 1).
Whether higher dosages are more efficacious or reduce the risk

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 of resistance, or even whether ampicillin-sulbactam should be
used in combination with other agents (as recommended by
others), is yet to be determined [8].
Carbapenems. Despite the absence of randomized con-
trolled trials, the carbapenems (imipenem, meropenem, or do-
ripenem) remain one of the most important therapeutic op-
tions for serious infections caused by multidrug-resistant A.
baumannii. They have excellent bactericidal activity and sta-
bility toward a range of b-lactamases. Unfortunately, increasing
carbapenem resistance is creating therapeutic challenges, es-
pecially considering that most A. baumannii strains that are
resistant to the carbapenems are also resistant to the majority
of other antibiotics (except the polymyxins or tigecycline). Sus-
ceptibility to the carbapenems ranges from 190% to as low as
32% depending on the geographic region and the carbapenem
tested [12–16]. Discordance in susceptibilities between the car-
bapenems is well described. Norskov-Lauritsen et al [13] re-
ported that 13% of isolates were resistant to imipenem, yet
23% were resistant to meropenem. Conversely, Ikonomidis et
al [16] reported that 59% of isolates were meropenem suscep-
tible, whereas only 32% were imipenem susceptible. A clear
understanding of local susceptibility patterns and sufficient lab-
oratory support to test the carbapenems of interest are required
when deciding on treatment. One cannot equate imipenem
results with meropenem. The clinical impact of discordant re-
sults is exemplified in the case report by Lesho et al [17]. They
describe a fatal case of A. baumannii pneumonia in which
meropenem was administered on the basis of imipenem sus-
ceptibility, yet the isolate was later proven to be meropenem
resistant. Doripenem is a new carbapenem with equivalent in
vitro activity against A. baumannii isolates. There does not
appear to be any advantage of doripenem when compared with
imipenem and meropenem, however [18]. Discordant results
between doripenem and imipenem or meropenem have been
reported against a few isolates of A. baumannii [18].
Aminoglycosides. Amikacin and tobramycin are the 2
agents that appear to retain activity against many A. baumannii
isolates. As with all antimicrobial agents and multidrug-resis-
tant pathogens, resistance is increasing, and susceptibility test-
ing is required to ensure activity. A recent analysis of discordant
susceptibility testing by Akers et al [19] has generated some
significant concerns about automated testing for aminoglyco-
side activity against A. baumannii. The percentage of isolates
with amikacin susceptibility was reported as 53% by Vitek 2
(bioMérieux), compared with only 17% by Etest (AB Biodisk)
and broth microdilution [19]. Results were similar for tobra-
mycin, but gentamicin did not display any discordance. To-
bramycin maintained the highest overall susceptibility rates
[19].
Aminoglycosides are not often used as single agents for treat-
ment, and the toxicity profiles often hinder their use (especially
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for longer treatment courses). There has been much debate on
the usefulness of these agents in pneumonia, but a detailed
review of this issue is well beyond the scope of this article. One
study by Gounden et al [20] demonstrated tobramycin’s com-
parative activity and toxicity in treating A. baumannii infections
with that of colistin. In that study, 32 patients (retrospective
cohort) were found to have received therapy in each group.
They found no statistically significant difference in intensive
care unit mortality (total in-house mortality favored colistin),
increase in serum creatinine over baseline, or time to micro-
biologic clearance [20].
The efficacy of inhaled antibiotics, including aminoglyco-
sides, outside the cystic fibrosis population is of increasing
interest. Unfortunately, very little clinical data exists for inhaled
aminoglycosides (outside of cystic fibrosis patients). Tobi (No-
vartis Pharmaceuticals), a specific formulation of inhaled to-
bramycin, has been approved by the US Food and Drug Ad-
ministration (FDA) for pseudomonas infections in cystic
fibrosis patients only. Hallal et al [21] investigated the utility
of inhaled versus intravenous tobramycin, both in combination
with an intravenous b-lactam, in a pilot randomized study
(n p 10). All 5 patients in the inhaled tobramycin group sur-
vived, but only 3 survived in the intravenous tobramycin group.
It should be noted, however, that these 2 patients had higher
multiple organ dysfunction scores [21]. Historically, aminogly-
cosides have been used mostly in combination therapy, and at
least for Pseudomonas aeruginosa, monotherapy appears to be
inferior to other agents.
Polymyxins. Unfortunately, familiarity with this older class
of antibiotic is now increasing in many parts of the world. The
polymyxins include colistin or polymyxin E and polymyxin B,
and this class of drug has been a savior for the treatment of
highly drug-resistant gram-negative bacteria. Colistin is most
commonly used in the United States, and it is administered
intravenously as a pro-drug known as colistimethate sodium
(CMS). Colistin sulfate is used topically but, most importantly,
is also the form that should be used in the laboratory for
susceptibility testing. Current Clinical and Laboratory Stan-
dards Institute breakpoints for colistin are ⭐2 mg/mL (suscep-
tible) and ⭓4 mg/mL (resistant).
A wide range of observational studies have now been pub-
lished on the clinical efficacy and toxicity of colistin for treating
modern day gram-negative bacteria [4]. Efficacy ranges from
∼55% to 180% depending on the study and appears to be equal
to that of other antibiotics in similar populations. Nephrotox-
icity and neurotoxicity remain as key concerns for increasing
use in an era of multidrug-resistant pathogens [22]. Nephro-
toxicity is a particular issue for those with preexisting renal
impairment, the elderly population, and those who receive con-
comitant nephrotoxins. Many authors who have reported on
the use of colistin have been pleasantly surprised with its tol-
REVIEWS OF ANTI-INFECTIVE AGENTS • CID 2010:51 (1 July) • 81
 erability. As has been discussed elsewhere, dosing remains con-
fusing, because formulations differ between countries [23].
Current parenteral formulations in the United States are avail-
able as either Coly-Mycin M Parenteral (Parkdale Pharmaceu-
ticals) or generically via a variety of manufacturers. The rec-
ommended dosages are 2.5–5.0 mg/kg per day of colistin base
given in 2–4 divided doses (equivalent to 6.67–13.3 mg/kg per
day of CMS) in those with normal renal function. Additional
work is still required to determine the ideal dosing of intra-
venous colistin to maintain efficacy and minimize toxicity.
Promising data are available for the use of inhaled CMS as
adjunctive treatment for pneumonia caused by multidrug-re-
sistant A. baumannii. However, more data are still required.
Concerns about lung toxicity, drug distribution, alveolar pen-
etration, emergence of resistance, and selection for organisms
inherently resistant to colistin are all justified and still need
clarification [24]. According to a recent FDA health alert, those
prescribing nebulized CMS should use it immediately after
preparation to prevent build up of the active colistin form,
which can be toxic to the lungs.
Although A. baumannii meningitis remains an uncommon
health care–associated infection, its incidence is increasing, and
it is often caused by multidrug-resistant organisms [25]. Car-
bapenems should be used to treat these infections if the or-
ganism is susceptible, with or without an intrathecal or in-
traventricular aminoglycoside. For carbapenem-resistant cases,
intravenous polymyxin (colistin or polymyxin B) plus an in-
trathecal or intraventricular polymyxin or aminoglycoside, with
or without intravenous rifampin, would be recommended [25].
Multiple case series and reports have now been published on
the favorable efficacy and toxicity profile of intraventricular/
intrathecal colistin [25, 26]. Chemical meningitis appears to be
uncommon. The dosing recommended by the Infectious Dis-
eases Society of America for adults is 10 mg daily of colistin
or 5 mg daily of polymyxin B [27].
Tigecycline. Tigecycline is the first of a new class of anti-
biotics known as the glycylcyclines. It is a semisynthetic deriv-
ative of minocycline and inhibits the 30S ribosomal subunit.
Its advantage over other tetracycline antibiotics is its ability to
evade the traditional tetracycline-specific resistance mecha-
nisms—tet(A-E) and tet(K) efflux pumps and the tet(O) and
tet(M) determinants that provide ribosomal protection—and
therefore it has a broader spectrum of activity. Recent global
in vitro data suggest that the 90% minimum inhibitory con-
centration (MIC90) for carbapenem-resistant A. baumannii iso-
lates is 2 mg/mL [28]. Susceptibility breakpoints from the Clin-
ical and Laboratory Standards Institute have not yet been
determined. Despite tigecycline’s in vitro activity against A.
baumannii, clinical data remains limited. Studies are observa-
tional and are often clouded by the effects of combination
antibiotic therapy [29]. Favorable clinical responses have been
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reported for serious infections [30]. However, because of the
rapid movement of tigecycline into tissues after intravenous
administration, we would recommend avoiding tigecycline use
alone for A. baumannii bloodstream infections (especially if the
MIC is ⭓1 mg/mL) [31]. Mean maximum serum steady-state
concentrations are only 0.63 mg/mL because of the large volume
of distribution [4].
Tetracyclines. Minocycline and doxycycline are both avail-
able by intravenous infusion and minocycline is approved by
the FDA for use in acinetobacter infections. In vitro suscep-
tibility testing is required for each agent to demonstrate sus-
ceptibility. Tetracycline cannot be used as a surrogate marker,
because many tetracycline-resistant isolates prove to be sus-
ceptible to minocycline [32]. As with the aminoglycosides, Ak-
ers et al [33] also reported discordant susceptibility results be-
tween broth microdilution and Etest/disk diffusion among all
3 agents tested. A study by Hawley et al [34] examined 142 A.
baumannii isolates from US soldiers. They found that the MIC90
for minocycline was 4, compared with 8 for tigecycline and
116 for doxycycline, thus supporting the concept of clinical
use in A. baumannii infections [34]. Clinical data is surprisingly
limited for minocycline and doxycyline. One study demon-
strated success in 7 of 8 patients who received minocycline for
wound infections, and another study found 6 of 7 patients with
ventilator-associated pneumonia were successfully treated with
one of these agents [32].
COMBINATION THERAPY
A significant amount of time and energy has been devoted to
studying combination therapy for the treatment of A. bau-
mannii infection. Much of the current information is derived
from in vitro or animal studies. There are surprisingly limited
data from comparative studies involving human A. baumannii
infections. Petrosillo et al [35] produced a nice review on co-
listin versus combination therapy. They found only 4 relevant
clinical studies, and only 1 study demonstrated any statistical
significance with respect to mortality, favoring monotherapy.
The heterogeneity of combinations and infections studied, as
well as the small numbers of patients involved, makes inter-
pretation very difficult [35]. Bassetti et al [36] conducted a
prospective noncomparative study of colistin-rifampin com-
bination involving critically ill patients with pneumonia and
bacteremia. They observed a clinical and microbiological re-
sponse rate of 76% with a mortality rate of 21%. All findings
are considered to be within previously reported ranges of treat-
ment outcomes. The noncomparative nature of the study makes
any concrete conclusions difficult. Lee et al [37] reported suc-
cessful treatment with carbapenem-sulbactam combination
therapy in 4 patients (1 of whom received meropenem and 3
of whom received imipenem) despite all isolates showing re-
sistance to both agents. Falagas et al [38] conducted a retro-
 spective cohort study involving patients who were treated with
colistin versus colistin-meropenem. They found no difference
in outcomes between the 2 groups; however, the number of
monotherapy patients was small. Overall, there is far more in
vitro and in vivo data available than there is data from clinical
studies, which makes any direct applicability of the data to
clinical care problematic. To summarize the extensive in vitro
information, the most significant data on combination therapy
pertains to colistin and rifampin or a carbapenem [4, 39].
Because of the lack of well-controlled comparative trials of
combination therapy for A. baumannii infections, we cannot
make any specific recommendations related to the various
agents available for therapy.
PROLONGED INFUSION b-LACTAMS
Because of the emergence of broad-spectrum antibiotic resis-
tance in Acinetobacter species and the dearth of new antibac-
terials, greater emphasis has been placed on optimizing the use
of currently available agents. Significant attention has been jus-
tifiably directed toward using pharmacokinetic and pharma-
codynamic parameters to tailor antibacterial dosing. This log-
ical approach accounts for characteristics of the drug, the
pathogen, and the host. Despite the long-term knowledge and
understanding of time-dependent versus concentration-depen-
dent antimicrobial activity, physicians are only recently mod-
ifying their antibiotic dosing in an attempt to incorporate these
principles.
Clinical literature is emerging on the use of extended-infu-
sion b-lactams to treat gram-negative bacteria, especially with
cefepime, piperacillin-tazobactam, and the carbapenems (mer-
openem, imipenem, and doripenem). One of the key advan-
tages of extended-infusion b-lactams is the ability to achieve
drug concentrations above the MIC for a greater time for less-
susceptible organisms, especially those with an MIC between
4 mg/mL and 16 mg/mL. For example, Li et al [40] have shown
that the likelihood of achieving bactericidal target attainment
with meropenem, which equates to a T 1MIC of at least 40%,
increases from 64% to 90% when the infusion time of 1 g is
increased from 0.5 h to 3 h for an organism with an MIC of
4 mg/mL (susceptible breakpoint). Importantly, modeling stud-
ies that use data from patients with ventilator-associated pneu-
monia support such findings and have shown that, by increas-
ing the dose of meropenem to 2 g every 8 h and increasing
the infusion time to 3 h, bactericidal target attainment can be
achieved for organisms with an MIC of 16 mg/mL (intermediate
breakpoint) [41]. Data are also available for extended-infusion
imipenem. Both imipenem and meropenem have short half-
lives (⭐4 h), and this limits their usefulness for infusions be-
yond 3 h. Conversely, doripenem has a longer half-life [18]
and has been administered as an extended-infusion in licensing
studies. Despite modeling and retrospective clinical studies that
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have shown benefits for extended-infusion b-lactams [42], pro-
spective clinical trials are lacking. It must also be highlighted
that the pharmacokinetic and pharmacodynamic benefits of
extended-infusion b-lactams attenuate in patients with increas-
ing renal impairment, which is a common comorbidity in pa-
tients with Acinetobacter infection who are hospitalized in in-
tensive care units. Finally, it is unknown whether the use of
extended-infusion carbapenems will reduce the emergence of
antibiotic resistance in Acinetobacter; however, promising re-
sults exist for Pseudomonas aeruginosa [43].
SUMMARY
Acinetobacter infections remain difficult to treat. The prevalence
of drug-resistant strains is increasing, and treatment options
are increasingly limited. Effective therapy remains likely when
the organism is proven to be susceptible. Recent data would
suggest that, for some agents, a single testing method may result
in incorrect susceptibility results and lead the clinician to select
a potentially ineffective agent. Because of some of the unusual
and potentially toxic options, one must maintain a high index
of suspicion for A. baumannii infection and select empirical
therapy wisely. The challenge for the clinician is to combine
local susceptibility patterns with the agents that are most likely
to be effective. The use of combination therapy, whether em-
pirical or targeted, has yet to be demonstrated, and hopefully
future studies will elucidate a greater number of definitive and
practical options.
Acknowledgments
Potential conflicts of interest. A.P. has been a consultant for Abbott
Molecular and Ortho-McNeil-Janssen. J.F.: no conflicts.
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