Acinetobacter R E V I E W S O F A... I N V I T E D A R T... Joel Fishbain

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
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, bacteremia, wound infections, urinary tract infections, and meningitis
has been well described [1]. Risk factors associated with colonization or infection (which can be difficult to distinguish)
include prolonged hospitalization, intensive care unit admission, recent surgical procedures, antimicrobial agent exposure,
central venous catheter use, prior hospitalization, nursing home
residence, and local colonization pressure on susceptible patients [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 resistance is common with health care–associated A. baumannii
infections. The impressive number of acquired mechanisms of
resistance makes selection of an appropriate empirical antimicrobial 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
[email protected]).
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 reviewed in Peleg et al [4]. Degradation enzymes against b-lactams, modification enzymes against aminoglycosides, altered
binding sites for quinolones, and a variety of efflux mechanisms and changes in outer membrane proteins have been reported. Essentially, any and all of these elements can be combined to result in a highly drug-resistant, and at times panresistant, opportunistic pathogen [4].
Attributable mortality has been difficult to assess for an organism that appears to be as much a colonizer as it is a true
pathogen. Although one cannot argue against the pathogenicity of an organism that is identified in bloodstream infections,
A. baumannii is often identified in the sputum samples of patients with mechanical ventilation. This quandary of pathogenicity 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 studies did not demonstrate a statistically significant difference between 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 options using available clinical data (Table 1). The reader is encouraged to review the in vitro and animal studies for additional information.
REVIEWS OF ANTI-INFECTIVE AGENTS • CID 2010:51 (1 July) • 79
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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 wellcontrolled 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.
Table 1. Antimicrobial Agents for the Treatment of Acinetobacter Infections
a
Medication
Dosage
Route
Toxicity
Comments
Sulbactam (amp/sulb in
the United States)
6 g per day
IV
Dermatologic, GI, nephritis
Adjust for renal function; daily dose based
on sulbactam
Imipenem-cilastatin
500 mg every 6 h up to 1 g
every 6–8 h
IV
Phlebitis, GI, anaphylaxis, seizures,
nephritis
Extended infusions have been used, limited data
Meropenem
500 mg to 1 g every 8 h
IV
GI, headache, dermatologic, hematologic, angioedema, seizure
Extended infusions have been used, limited data
Doripenem
500 mg every 8 h
IV
Dermatologic, GI, anemia, anaphylaxis, seizure
Consider extended infusion
Regimen 1
15 mg/kg daily
IV
Nephrotoxicity, ototoxicity, neuromuscular blockade
Regimen 2
30 mg
Amikacin
IVent
Tobramycin
4–7 mg/kg daily
Regimen 2
300 mg (1 ampule) twice daily
Regimen 3
5– 20 mg
IV
Nephrotoxicity, ototoxicity, neuromuscular blockade
IH
IT/IVent
Peak and trough measurements as appropriate for dosing regimen selected
Tobi inhaled formulation
Not for children
Not FDA approved for this route of
administration
Colistin (colistimethate)
Regimen 1
5 mg/kg/day, 2–4 divided
doses
IV
Nephrotoxicity and neurotoxicity
Additional data still required on ideal
dosing
Regimen 2
1–3 million IU every 8 h
IH
Must be used immediately after reconstitution to prevent accumulation of colistin–lung toxicity
1 million IU is 80 mg of colistimethate. A
variety of doses used in studies
Polymyxin B [25]
50,000 units daily (5 mg
IT
Meningeal irritation
Has been used as intraventricular injection 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 every 12 h
IV
GI, shock, pancreatitis, anaphylaxis
Avoid use in blood stream infections due
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; limited 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 possesses the greatest intrinsic bactericidal activity against A. baumannii isolates [4]. Results of clinical investigations have documented the efficacy of sulbactam (commercially available in
the United States in combination with ampicillin) in mild-tosevere 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 receiving mechanical ventilation demonstrated clinical improvement using ampicillin-sulbactam at a dosage of 3 g of amicillin
and 1.5 g of sulbactam intravenously every 6 or 8 h. Sulbactamcontaining regimens appeared to be comparable to regimens
80 • CID 2010:51 (1 July) • REVIEWS OF ANTI-INFECTIVE AGENTS
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 statistically 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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Regimen 1
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 comparative 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 microbiologic clearance [20].
The efficacy of inhaled antibiotics, including aminoglycosides, outside the cystic fibrosis population is of increasing
interest. Unfortunately, very little clinical data exists for inhaled
aminoglycosides (outside of cystic fibrosis patients). Tobi (Novartis Pharmaceuticals), a specific formulation of inhaled tobramycin, has been approved by the US Food and Drug Administration (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 survived, 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, aminoglycosides 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 Standards Institute breakpoints for colistin are ⭐2 mg/mL (susceptible) and ⭓4 mg/mL (resistant).
A wide range of observational studies have now been published 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. Nephrotoxicity and neurotoxicity remain as key concerns for increasing
use in an era of multidrug-resistant pathogens [22]. Nephrotoxicity is a particular issue for those with preexisting renal
impairment, the elderly population, and those who receive concomitant nephrotoxins. Many authors who have reported on
the use of colistin have been pleasantly surprised with its tolREVIEWS OF ANTI-INFECTIVE AGENTS • CID 2010:51 (1 July) • 81
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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 controlled trials, the carbapenems (imipenem, meropenem, or doripenem) remain one of the most important therapeutic options for serious infections caused by multidrug-resistant A.
baumannii. They have excellent bactericidal activity and stability toward a range of b-lactamases. Unfortunately, increasing
carbapenem resistance is creating therapeutic challenges, especially 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). Susceptibility 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 carbapenems is well described. Norskov-Lauritsen et al [13] reported 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 susceptible, whereas only 32% were imipenem susceptible. A clear
understanding of local susceptibility patterns and sufficient laboratory 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 results 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 susceptibility, 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-resistant pathogens, resistance is increasing, and susceptibility testing 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 aminoglycoside activity against A. baumannii. The percentage of isolates
with amikacin susceptibility was reported as 53% by Vitek 2
(bioMe´rieux), compared with only 17% by Etest (AB Biodisk)
and broth microdilution [19]. Results were similar for tobramycin, but gentamicin did not display any discordance. Tobramycin maintained the highest overall susceptibility rates
[19].
Aminoglycosides are not often used as single agents for treatment, and the toxicity profiles often hinder their use (especially
82 • CID 2010:51 (1 July) • REVIEWS OF ANTI-INFECTIVE AGENTS
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 available by intravenous infusion and minocycline is approved by
the FDA for use in acinetobacter infections. In vitro susceptibility testing is required for each agent to demonstrate susceptibility. Tetracycline cannot be used as a surrogate marker,
because many tetracycline-resistant isolates prove to be susceptible to minocycline [32]. As with the aminoglycosides, Akers et al [33] also reported discordant susceptibility results between 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 demonstrated 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. baumannii 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 colistin 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 interpretation very difficult [35]. Bassetti et al [36] conducted a
prospective noncomparative study of colistin-rifampin combination involving critically ill patients with pneumonia and
bacteremia. They observed a clinical and microbiological response rate of 76% with a mortality rate of 21%. All findings
are considered to be within previously reported ranges of treatment outcomes. The noncomparative nature of the study makes
any concrete conclusions difficult. Lee et al [37] reported successful treatment with carbapenem-sulbactam combination
therapy in 4 patients (1 of whom received meropenem and 3
of whom received imipenem) despite all isolates showing resistance to both agents. Falagas et al [38] conducted a retro-
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erability. As has been discussed elsewhere, dosing remains confusing, because formulations differ between countries [23].
Current parenteral formulations in the United States are available as either Coly-Mycin M Parenteral (Parkdale Pharmaceuticals) or generically via a variety of manufacturers. The recommended 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 intravenous 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-resistant A. baumannii. However, more data are still required.
Concerns about lung toxicity, drug distribution, alveolar penetration, 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]. Carbapenems should be used to treat these infections if the organism is susceptible, with or without an intrathecal or intraventricular aminoglycoside. For carbapenem-resistant cases,
intravenous polymyxin (colistin or polymyxin B) plus an intrathecal 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 Diseases 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 antibiotics known as the glycylcyclines. It is a semisynthetic derivative of minocycline and inhibits the 30S ribosomal subunit.
Its advantage over other tetracycline antibiotics is its ability to
evade the traditional tetracycline-specific resistance mechanisms—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 concentration (MIC90) for carbapenem-resistant A. baumannii isolates is 2 mg/mL [28]. Susceptibility breakpoints from the Clinical and Laboratory Standards Institute have not yet been
determined. Despite tigecycline’s in vitro activity against A.
baumannii, clinical data remains limited. Studies are observational and are often clouded by the effects of combination
antibiotic therapy [29]. Favorable clinical responses have been
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
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 empirical 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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