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REVIEW ARTICLE
Carbapenem resistance in Acinetobacter baumannii, and
their importance in hospital-acquired infections: a scientific
review
M. Nguyen
1
and S.G. Joshi
1,2
1 Center for Surgical Infections, Drexel University School of Biomedical Engineering, Science & Health Systems, Philadelphia, PA, USA
2 Institute of Molecular Medicine and Infectious Diseases, Center for Surgical Infections, Drexel University, Philadelphia, PA, USA
Keywords
Acinetobacter baumannii, antimicrobial
susceptibility test, biofilm, carbapenem,
carbapenem resistance, genotypic test,
infection control, mobile genetic element,
multidrug resistance, nosocomial infection,
phenotypic test, virulence.
Correspondence
Suresh G. Joshi, 3141 Chestnut Street, Suite:
Bossone-718, Philadelphia, PA 19104, USA.
E-mail: SGJ24@drexel.edu; surejoshi@yahoo.-
com
2021/2785: received 31 December 2020,
revised 30 March 2021 and accepted 4 May
2021
doi:10.1111/jam.15130
Summary
Carbapenem is an important therapy for serious hospital-acquired infections
and for the care of patients affected by multidrug-resistant organisms,
specifically Acinetobacter baumannii; however, with the global increase of
carbapenem-resistant A. baumannii, this pathogen has significantly threatened
public health. Thus, there is a pressing need to better understand this pathogen
in order to develop novel treatments and control strategies for dealing with A.
baumannii. In this review, we discuss an overview of carbapenem, including its
discovery, development, classification and biological characteristics, and its
importance in hospital medicine especially in critical care units. We also
describe the peculiarity of bacterial pathogen, A.baumannii, including its
commonly reported virulence factors, environmental persistence and
carbapenem resistance mechanisms. In closing, we discuss various control
strategies for overcoming carbapenem resistance in hospitals and for limiting
outbreaks. With the appearance of strains that resist carbapenem, the aim of
this review is to highlight the importance of understanding this increasingly
problematic healthcare-associated pathogen that creates significant concern in
the field of nosocomial infections and overall public health.
Introduction
Carbapenems are antimicrobial agents that are important
in the treatment of nosocomial infections since they have
the most comprehensive spectrum of activity as well as
the most prominent potency against Gram-positive and
Gram-negative bacteria (Papp-Wallace et al. 2011). For
these reasons, they are usually prescribed as antibiotics of
last resort for critically ill patients. In recent years, Acine-
tobacter species have become a significant cause of critical
healthcare-associated diseases and infections (Lima et al.
2019). Acinetobacter baumannii is predominantly related
to hospital-acquired infections globally and is an aerobic
Gram-negative pathogen that leads to infections of
the skin, bloodstream, urinary tract and other soft tis-
sues (Joshi and Litake 2013; Lin and Lan 2014; Lee
et al. 2017). Unfortunately, the global emergence of
A.baumannii that is resistant against carbapenem endan-
gers human health and modern healthcare systems
(Harding et al. 2017). In order to overcome endemic sit-
uations and control future outbreaks or further develop-
ment of resistance to carbapenem, an understanding of
carbapenems including its background, chemical or bio-
logical properties, role in clinical use, as well as knowl-
edge of A.baumannii, including its epidemiology,
virulence factors and carbapenem resistance mechanisms
is crucial. This may prompt insight into the development
of new agents or novel therapeutic strategies for dealing
with challenges associated with carbapenem-resistant A.
baumannii (CRAB) and for preventing this pathogen
from further disseminating.
Carbapenem
Development and history of carbapenem
Safe and effective antibiotics play an important role in
medical care and their development remains one of the
Journal of Applied Microbiology ©2021 The Society for Applied Microbiology 1
Journal of Applied Microbiology ISSN 1364-5072
most important advances for healthcare systems. With
the introduction of these agents, the rate of morbidity
and mortality associated with a number of life-
threatening diseases has significantly decreased and
antibiotics have become the cornerstone for therapy
related to bacterial infection (Rice 2008). Ever since the
first b-lactam, penicillin, was introduced to clinical medi-
cine as an option to treat a variety of bacterial infections,
b-lactam antibiotics are usually selected as the preferred
antimicrobial agents (Drawz and Bonomo 2010). All
b-lactams have a b-lactam ring, and they bind to and
inactive penicillin-binding proteins (PBPs), which medi-
ate formation of bacterial cell wall (Meletis 2015).
However, in the late 1960s, the appearance of bacterial
b-lactamases, which were unaffected by b-lactam antibi-
otics, challenged penicillin’s effectiveness, which provoked
the search for additional b-lactam antibiotic derivatives
to maintain the usefulness of b-lactam antibiotics
(Papp-Wallace et al. 2011).
To deal with the clinical threat of b-lactamase, the
research and development of b-lactamase inhibitors
occurred, and researchers discovered the first one by
1976. Streptomyces clavuligerus is a Gram-positive bac-
terium that naturally produces broad-spectrum olivanic
acids, which have carbapenem-like structure. Unfortu-
nately, since olivanic acids were chemically unstable and
did not penetrate bacterial cells effectively, researchers did
not conduct further investigation (Papp-Wallace et al.
2011). Later in the same year, researchers discovered two
b-lactamase inhibitors that were superior to the original
olivanic acids: clavulanic acid from S.clavuligerus and
thienamycin from culture broths of the soil organism,
Streptomyces cattleya (Papp-Wallace et al. 2011; Henry
2019).
The earliest known carbapenem that later acted as the
model for the development of subsequent carbapenems is
thienamycin (Papp-Wallace et al. 2011). It has stable,
broad-spectrum antibacterial and inhibitory actions
against of b-lactamase but is unfortunately chemically
unsteady in aqueous solution since it quickly decomposes
in the presence of water (Henry 2019). It is also sensitive
to levels of pH greater than 80, in addition to being very
responsive to nucleophiles, such as hydroxylamine, cys-
teine and amine. For these reasons, thienamycin had little
clinical use. Its chemical instability consequently triggered
further research and development of more chemically
stable derivatives (Papp-Wallace et al. 2011). In 1985,
researchers developed the first carbapenem that was
authorized in the United States for treatment of complex
microbial infections: a more stable N-formimidoyl deriva-
tive of thienamycin called imipenem that is less sensitive
to base hydrolysis in solution (Papp-Wallace et al. 2011;
Henry 2019). During the search for safer carbapenems
with a more comprehensive spectrum of activity, several
new carbapenems were identified such as meropenem,
ertapenem and doripenem (Papp-Wallace et al. 2011).
Types and classification of carbapenem
Among the wide variety of b-lactam antimicrobials, car-
bapenems are considered the most effective class with the
most extensive spectrum of antimicrobial activity and
excellent safety and tolerability profiles. Therefore, they
are widely prescribed to treat serious infections triggered
by multidrug resistant (MDR) organisms. Those that are
approved and available for clinical use include imipenem,
meropenem, ertapenem and doripenem (Kattan et al.
2008).
With data from clinical trials and clinical use, a classifi-
cation system for carbapenems was created based on their
antimicrobial activity. Carbapenems from group 1, such
as ertapenem, are inefficient against non-fermentative
Gram-negative bacilli and may be more suitable for
community-acquired infections (Shah 2008; Yoon et al.
2014). Agents from group 2, such as meropenem, imipe-
nem and doripenem, have broad-spectrum actions, are
also active against non-fermentative Gram-negative bacilli
and are effective against nosocomial infections (Kattan
et al. 2008; Shah 2008). Group 3 carbapenems, such as
Tomopenem and Razupenem (PZ-601), are potent
against non-fermentative Gram-negative bacilli and Sta-
phylococcus aureus which are resistant against methicillin
(Shah 2008).
The oldest carbapenem that has been used by more
than 26 million patients over the past two decades is imi-
penem (Tahri et al. 2017). In addition to exhibiting high
chemistry for PBPs, it has good stability against
b-lactamases and is an effective therapy for Pseudomonas
aeruginosa and Acinetobacter species, which are usually
related to hospital-acquired critical infections; unfortu-
nately, since 1986, therapies involving imipenem have
become more ineffective (Kattan et al. 2008). Overall, this
carbapenem is marginally more potent against Gram-
positive bacteria compared to other agents. In addition,
since it is vulnerable to dehydropeptidase I (DHP-I), a
renal tubular dipeptidase enzyme which causes its degra-
dation, imipenem is usually co-administered with cilas-
tatin or betamipron. Cilastatin is a competitive
antagonist that also works to protect the kidneys from
harmful damage generated by higher doses of imipenem
(Elshamy and Aboshanab 2020). The United States Food
and Drug Administration (US FDA) does not authorize
the use of imipenem to treat meningitis or infections
related to the central nervous system since it prompts sei-
zures in people with critical risk factors including renal
failure or structural brain disease (Kattan et al. 2008).
Journal of Applied Microbiology ©2021 The Society for Applied Microbiology2
Carbapenem resistance and Acinetobacter M. Nguyen and S.G. Joshi
Meropenem was discovered in 1995 with the addition
of 1-b-methyl substituent at position 1, C-1. Unlike imi-
penem, cilastatin does not need to be administered
simultaneously since the 1-b-methyl group makes it
unsusceptible to the hydrolysis of DHP-I (Shah and
Isaacs 2003). In order to treat bacterial meningitis in
adults and children older than 3 months, meropenem
may be used since the US FDA has approved its usage.
Its range of action resembles that of imipenem, including
P. aeruginosa and Acinetobacter species, but it is some-
what more potent against Gram-negative aerobic bacteria
(Kattan et al. 2008). Meropenem, one of the smallest
b-lactam antibiotics, is a very broad-spectrum due to its
compact size and zwitterion state which enables it to
easily penetrate the cell membrane of multiple Gram-
negative bacilli (Hellinger and Brewer 1999). Over the
years, evidence of meropenem’s clinical efficacy seen
through its widespread clinical use has led physicians to
consider this carbapenem as one of the most dependable
and accessible drugs that can treat critically ill patients
with hospital-acquired infections (Shah and Isaacs 2003).
Ertapenem, a 1-b-methyl carbapenem discovered in
2001, has potent actions against a wide spectrum of bac-
terial pathogens such as Gram-negative enteric producing
extended spectrum b-lactamases (ESBLs) and/or AmpC-
type b-lactamases (Shah and Isaacs 2003; Kattan et al.
2008). In comparison to imipenem and meropenem, erta-
penem is more resistant to DPH-I inactivation than imi-
penem but less active against P. aeruginosa, Acinetobacter
species and Enterococci which is the reason for its lack of
indication in clinical situations with suspected nosoco-
mial infection (Kattan et al. 2008; Shah 2008). Since it
has a lengthier elimination half-life and a once-a-day dos-
ing regimen, ertapenem is an essential therapy for
community-acquired bacterial infections where there is
most likely an assorted flora of anaerobes and aerobes,
for example community-acquired pneumonia and com-
plicated intra-abdominal, skin or urinary tract infections
(Kattan et al. 2008; Shah 2008).
Similar to meropenem, doripenem is resistant to DPH-
I inactivation and has stable b-lactamase activity (Bassetti
et al. 2013). It also shows stable activity against Staph.
aureus, but is not as active against methicillin-resistant S.
aureus,Enterococcus faecium and vancomycin-resistant en-
terococci (VRE). In 2007, the US FDA accepted merope-
nem to treat complicated urinary tract or intra-
abdominal infections and pyelonephritis (Bassetti et al.
2013).
Etymology and chemistry of carbapenem
Carbapenem is defined as a class of semi-synthetic broad-
spectrum b-lactam antibiotics that is similar in structure
to penicillin. However, unlike penicillin, there is a carbon
atom substitution for a sulphur atom at C-1 and an
unsaturated bond between C-2 and C-3 at five-membered
a-ring, which creates a double bond on the pentane (Lo
et al. 2008; Henry 2019). It is important to note that car-
bapenems possess a trans configuration of hydroxyethyl
at C-6 which contributes to greater stability against
b-lactamase hydrolysis as compared to the cis configura-
tion of penicillins and cephalosporins as seen in Fig. 1
(Lo et al. 2008). This 6-trans-hydroxyethyl group on car-
bapenem is a key component for carbapenem activity and
stability (Lo et al. 2008). The chemical structures of four
FDA-approved carbapenems are shown in Fig. 2.
Biology of carbapenem
Mechanism of action
Since carbapenems are a part of b-lactams, they cannot
readily diffuse past the cell walls of bacteria. Instead, they
invade Gram-negative bacteria by moving between por-
ins, otherwise known as outer membrane proteins
(OMPs) (Papp-Wallace et al. 2011). Carbapenem then
exhibits bactericidal activity by binding to PBPs such as
enzymes with high molecular weight—PBP1a, 1b, 2 and
3 (Breilh et al. 2013). PBPs are cytoplasmic membrane
R2
R2
R2
H
HHHH
H
S
SR3
COOH COOH COOH
R1
NNN
R1
R1
OOO
Figure 1 Core chemical structures of cephalosporin, penicillin and carbapenem from left to right. Note: Trans configuration of hydroxyethyl
group at the C-5 and C-6 bond of carbapenem is important for its stability and potency versus cis configuration of penicillin and cephalosporin.
Journal of Applied Microbiology ©2021 The Society for Applied Microbiology 3
M. Nguyen and S.G. Joshi Carbapenem resistance and Acinetobacter
proteins in charge of forming peptidoglycan in the cell
wall of bacteria and maintaining the bacterial cell wall
(Lister 2007). Since carbapenems structurally resemble
acylated D-alanyl-D-alanine, they can bind irreversibly to
the active site of the PBPs. When b-lactam molecule
binds to PBPs, bacteria is prevented from completing
transpeptidation or other peptidase reactions of peptido-
glycan layer, thereby severing the formation of its cell
walls (Elshamy and Aboshanab 2020). Autolysin activities
subsequently leads to cell death of the bacteria. Autolysins
are a group of bacterial surface enzymes that generate
nicks in cell walls which become sites where new peptido-
glycan units can attach. As a result of obstruction of cell
wall formation by b-lactam agents as well as self-
destruction of cell walls, the cell membrane extrudes from
the weak spots in the cell wall (Elshamy and Aboshanab
2020). Because the membrane is then too weak to prevent
the hypertonic cell from bursting by osmotic shock, the
cell eventually ruptures due to osmotic pressure.
Carbapenem’s affinity for specific PBPs varies by spe-
cies and strains of bacteria; thus, carbapenems are distin-
guishable based on different relationships with PBPs (Lo
et al. 2008). The effectiveness of carbapenems can be
attributed to its ability to bind to and associate with
many of the vital PBPs of Gram-negative bacteria (Lister
2007). In addition, an important attribute that differenti-
ates carbapenems from other b-lactams, such as peni-
cillins and cephalosporins, is that carbapenem has
stronger affinity for PBP-1a and PBP-1b, a chemical
interaction that corresponds to quicker bacterial killing
and an increase in the death rate of pathogens such as P.
aeruginosa and Escherichia coli. Affinity for PBP1a or
PBP1b distinguishes carbapenems from other b-lactams,
whereas affinity for PBP-2 or PBP-3 of Gram-negative
bacteria differentiates carbapenems from one another
(Lister 2007). For example, imipenem has the strongest
liking for PBP2, followed by PBP-1a and PBP-1b, and
PBP-3. On the other hand, ertapenem and meropenem
exhibit strongest affinity for PBP-2, followed by PBP-3,
but also PBP-1a and PBP-1b. Doripenem binds to PBP-1,
PBP-2, PBP-4 in S.aureus, PBP-3 in P.aeruginosa and
PBP-2 in E.coli (Zhanel et al. 2007). The variability in
binding affinities of carbapenems for different PBPs may
explain the differences in antimicrobial activity (Lo et al.
2008).
Microbiological activity
Carbapenems demonstrate a wider range of antimicrobial
activity than penicillins, cephalosporins or b-lactam/b-
lactamase inhibitor combinations. As mentioned previ-
ously, different carbapenems have different potencies
against a variety of Gram-negative organisms and anaer-
obes and Gram-positive aerobes. For example, imipenem
and doripenem show potent activities against Gram-
positive bacteria, whereas ertapenem, meropenem and
doripenem are effective against Gram-negative organisms
OH
H
H
H
HHH
H
H
CH3CH3
H3C
H3C
H3C
H3C
H3C
CH3
NH
OH
S
O
O
O
O
OH
OH
OH
OH
OH
OH
N
N
N
N
NCH3
NH
NH
HN
HN
S
NH
HN S
S
S
O
O
O
O
O
O
OH
O
O
O
NH2
Figure 2 Chemical structures of a few carbapenems which have been approved by the FDA: doripenem (top left), ertapenem (top right), mero-
penem (bottom left) and imipenem (bottom right).
Journal of Applied Microbiology ©2021 The Society for Applied Microbiology4
Carbapenem resistance and Acinetobacter M. Nguyen and S.G. Joshi
(Papp-Wallace et al. 2011). Meropenem is moderately
more potent against Gram-negative organisms than imi-
penem, whereas the latter has better activity against
Gram-positive pathogens (Lo et al. 2008). Meanwhile,
doripenem is more effective against Gram-negative
organisms than imipenem and is the most effective car-
bapenem against penicillin-resistant streptococci (Lo
et al. 2008). While ertapenem has equivalent activity
against many Gram-positive and Gram-negative aerobes
and anaerobes as other carbapenems, it is not as effective
against P.aeruginosa,Acinetobacter sp. and Enterococcus
species (Lo et al. 2008).
Importance of carbapenem
b-Lactams are one of the most prescribed antimicrobial
agents in clinical medicine and in community settings
due to their efficacy and safety; carbapenems, specifically,
are the most commonly used group of antibiotics as pro-
ven by their importance in clinical practice (Kattan et al.
2008). Carbapenems are the foundation of antibiotic
therapy and drug of choice for complicated, severe bacte-
rial infections (Patrier and Timsit 2020). They can also
work in combination with other agents that target Gram-
positive bacteria in order to treat significant nosocomial
infections (Rahal 2008). Carbapenems are indicated in
patients with lower respiratory tract, skin and soft tissue,
central nervous system, urinary tract, joint, muscle, gyne-
cologic, obstetric, and abdominal infections or in man-
agement of febrile neutropenia and problems due to
cystic fibrosis (Lo et al. 2008). The global consumption
rate of carbapenem from 2000 to 2010 increased by 45%
(Patrier and Timsit 2020). In addition, the third most
used antibiotic globally for community-acquired infec-
tions in intensive care unit (ICU) (107%) and the first
most commonly used antibiotic for nosocomial infections
(215%) are carbapenems (Patrier and Timsit 2020).
Carbapenems are commonly used in hospitals since
they have the most comprehensive antibacterial spectrum
and strongest activity against Gram-positive and Gram-
negative bacteria among all b-Lactam that are currently
available (Papp-Wallace et al. 2011; Patrier and Timsit
2020). They are preferred over other types of antimicro-
bials for treatment of invasive or life-threatening condi-
tions because of their concentration-independent bacteria
killing effect (Codjoe and Donkor 2017). They also boast
a superb safety profile and are generally better tolerated
by patients, with allergic reactions being the most com-
mon adverse effect in carbapenem treatment (Kattan
et al. 2008). Since carbapenems are less detrimental than
other last-resort drugs such as polymyxins, they are more
commonly prescribed (Meletis 2015). In addition, they
are mostly unaffected to hydrolysis by most b-lactamases
and still target PBPs (Papp-Wallace et al. 2011; Patrier
and Timsit 2020). Overall, they are usually prescribed as
the last-line antibiotics for critically ill patients or other
patients suspected of having resistant bacteria since they
have good stability against many b-lactamases and are
usually successful in treating severe nosocomial infections
and infections generated by pathogens such as A.Bau-
mannii (Meletis 2015).
Acinetobacter baumannii
Acinetobacter baumannii is a bacterial pathogen responsi-
ble for nosocomial infections in the healthcare system,
particularly in ICUs. Due to the recent rise in infections
and outbreaks caused by MDR A. baumannii, it is impor-
tant to have knowledge and understanding of this patho-
gen in order to find effective ways for infection control
and for treating critically ill patients that have been
infected by this pathogen (Joshi et al. 2003; Lee et al.
2017). Figure 3 outlines a few features of A.baumannii
including its virulence factors, its mechanisms of car-
bapenem resistance and different treatment options that
will be further discussed in the sections below (Lo et al.
2008).
Taxonomy of Acinetobacter baumannii
The genus Acinetobacter was first accepted in 1968 as result
of bacteriologist Paul Baumann’s publication and was later
officially acknowledged in 1971 by the Taxonomy of Mor-
axella and Allied Bacteria (Howard et al. 2012). The genus
is described as Gram-negative, strictly aerobic, indole-
negative, non-fastidious, non-motile, catalase-positive,
oxidase-negative bacteria, citrate positive with a DNA G+C
content of 39–47% (Almasaudi 2018). There are currently
over 50 designated Acinetobacter species, with the majority
being non-pathogenic (Harding et al. 2017). The members
of the genus that are most relevant in clinic have similar
phenotypic and genotypic similarities and are therefore
often considered the Acinetobacter calcoaceticus–baumannii
(Acb) complex (Schleicher et al. 2013). There are five
pathogenic and one non-pathogenic species in the Abc
complex: A.baumannii,A.nosocomialis,A.pittii,A.seifertii
and A.dijkshoorniae, and lastly A.calcoaceticus (non-
pathogenic). However, the most clinically relevant is A.
baumannii (Harding et al.2017).
At the species level, A. baumannii are Gram-negative,
catalase-positive, oxidase-negative, non-motile, non-
fermenting coccobacilli. They resemble small Gram-
negative rods with challenging de-staining, which often
leads to their misidentification as Gram-positive (Howard
et al. 2012). With the rise in resistant Acb strains, it is
important to correctly identify A. baumannii isolates at
Journal of Applied Microbiology ©2021 The Society for Applied Microbiology 5
M. Nguyen and S.G. Joshi Carbapenem resistance and Acinetobacter
the species level to investigate A. baumannii epidemics.
Early epidemiological studies of Acinetobacter strains
adopted by Bouvet and Grimont (1987) involved the use
of biotyping system that relied on gelatinase production,
haemolysis and acid production from glucose for identifi-
cation of Acinetobacter species (Bouvet and Grimont
1987). Unfortunately, phenotypic testing on its own does
not cover all the variability in phenotypes and is not as
effective in identifying the more recent genomic strains of
Acinetobacter (Nemec et al. 2000; Howard et al. 2012). In
addition to phenotypic methods, genotypic methods can
also help with identifying species with the application of
genome-wide information and a variety of molecular typ-
ing methods, such as core genome multilocus sequencing
typing (cgMLST) and Pasteur’s 7-gene MLST method of
classifying Acinetobacter isolates of the Acb complex
(Gaiarsa et al. 2019). Other advanced molecular diagnos-
tic methods that can be used for identifying different spe-
cies include amplified 16S rRNA gene restriction analysis
(ARDRA), high-resolution fingerprint analysis by ampli-
fied fragment length polymorphism (AFLP) and matrix-
associated laser desorption ionization-time of flight
(MALDI-TOF) mass spectrometry for identification of
species-specific outer membrane parts of each member of
the Acb complex (Howard et al. 2012; Harding et al.
2017).
Natural habitats and epidemiology of Acinetobacter
baumanii
Acinetobacter genus members are believed to be ubiqui-
tous in nature due to their ability to recover from soil,
water, animals or humans; however, they are not exclu-
sively found in the environment. For example, A.bau-
mannii mostly in-habitats in hospital environment,
specifically in ICUs of both adults and neonates, and
burn, neurosurgery, surgical, medical and oncology units.
Acinetobacter baumannii most frequently isolated from
wounded skin and tissues, respiratory system (in the
pharynx, trachea or bronchi), bloodstream and central
nervous system. It is also related to skin and tissue infec-
tions at surgical sites and catheter-associated urinary tract
infections (Harding et al. 2017). The common factor for
those scenarios is a break in the anatomical barrier which
allows A.Baumannii to directly enter the affected area.
Overall, A.Baumannii is responsible for many hospital-
acquired infections across several sites in a patient’s body
but often presents itself as ventilator-associated pneumo-
nia (VAP) or bloodstream infections (Joshi et al. 2006;
Harding et al. 2017). Pneumonia threatens patient depen-
dent on mechanical ventilation since A.baumannii can
exteriorly create biofilms on endotracheal tube which
results in excessive colonization in the lower respiratory
Mechanisms of carbapenem
resistance in Acinetobacter
baumannii
Virulence factors
Overview of Adnetobacter baumannii
Overcoming Acinetobacter baumannii resistance
Therapeutic options
Alterations in penicillin-binding proteins
Loss of outer membrance porins
Overexpression of efflux pumps
Synthesis of carbapenemases
Capsular polysaccharides coverings
Biofilm formation
Proteins (AbOmpA, RecA)
Bacterial motility
Novel antibiotic
development
Novel antibiotic
development
Knowledge of:
Effective
combination
therapy
Leads
to
Leads
to
Leads
to
Polymyxin (colistin)
β-lactamase inhibitors and carbapenems
Tetracyclines
Other antibiotics (cefiderocol, fosfomycin)
Alternative therapies (bacteriophage,
antimicrobial peptides, vaccines)
Figure 3 Summary of important features in Acinetobacter baumannii such as its virulence factors and mechanisms of carbapenem resistance, as
well as important therapeutic options for decreasing the frequency and chances of outbreaks caused by this pathogen (adapted from Lee et al.
2017).
Journal of Applied Microbiology ©2021 The Society for Applied Microbiology6
Carbapenem resistance and Acinetobacter M. Nguyen and S.G. Joshi
tract (Howard et al. 2012). Based on reports from the
Healthcare Safety Network at the Centers for Disease and
Prevention, there is evidence of an increasing frequency
of A. baumannii nosocomial infections as shown by the
following percentages: 84% of VAP, 22% of central line-
related bloodstream infections, 12% of catheter-related
urinary tract infections and 06% of surgical site infec-
tions (Pogue et al. 2014).
Once A. baumannii strain is introduced to a hospital
ward by a patient who is already colonized, it can thrive
on dry surfaces under limited nutrient conditions. During
an outbreak, it can be recovered from several sites from
the patient’s environment, such as bed curtains, furniture,
handwashing sinks and other hospital equipment such as
ventilator tubing, arterial pressure transducers and
humidifiers. Modes of transmission may include air dro-
plets or skin of colonized patients; however, the bacteria
most commonly spread from hospital workers via hands.
Infected patients unknowingly carry it for days or weeks
until A. baumannii strain is identified in clinical speci-
mens. The overall interaction among A. baumannii
pathogen, hospital environment (surface and equipment),
high-risk patients and hospital staff is summarized in
Fig. 4 (Dijkshoorn et al. 2007; Giamarellou et al. 2008).
Virulence factors and environmental persistence of
Acinetobacter baumannii
Several virulence factors and environmental persistence
such as resistance to desiccation and disinfectants have
allowed A. baumannii to persist and thrive for an
extended period on dry surfaces (up to 4 months) and in
nosocomial environments that are usually deemed inhab-
itable to many other bacterial pathogens (Pogue et al.
2014; Harding et al. 2017).
Desiccation, oxidative stress and disinfection resistance
Acinetobacter baumannii has developed mechanisms to
resist stress associated with the desiccation and disinfec-
tion regimes of healthcare environments. Desiccation
resistance can be achieved through the capsular polysac-
charide covering in A. baumannii cells grown in biofilm
under desiccated conditions and through the capsule’s
water retaining ability in A. baumannii. Repeating carbo-
hydrate units make up these polysaccharides, which act
as glycan shields surrounding and protecting the bac-
terium from external threats.
When desiccation–rehydration of A. baumannii hap-
pens, DNA lesions occur and in order to protect itself
from the subsequent damage to the DNA from desicca-
tion–rehydration, A. baumannii depends on protein
RecA, an enzyme needed for the repair of homologous
recombination. There is approximately 50 times more
mutation prevalence during one round of desiccation–re-
hydration, which might explain the pathogen’s MDR
characteristics and ability to survive in dry conditions.
During periods of desiccation, oxidative stress can also
occur. To counter this oxidative stress, ISAba1 (an inser-
tion sequence (IS) element) upstream of katG (catalase
gene) is found in A. baumannii strains which enables the
pathogen to tolerate high levels of hydrogen peroxide. In
addition, chlorhexidine and other antiseptics that are
Transmission and Spread of Acinetobacter baumannii
Contact with contaminated
hospital environment
Respiratory secretion and droplets, open wounds, and scales of skin
of patients infected with Acinetobacter baumannii
- Contaminated surfaces and
equipment
- Contaminated hands of
healthcare staff, providers, and
caregivers
- Patient to healthcare
provider
- Patient to visitors
Person to person spread High risk patients
- Presence of mechanical
ventilation or indwelling
devices
- Stay in ICU and Wounds and
Burn unit
- Extended hospital stay
- Presence of underlying
chronic illness
- Immune-deficient and
susceptible hosts
Figure 4 A schematic of how epidemic Acinetobacter baumannii strains spread in hospitals (adapted from Dijkshoorn et al. 2007).
Journal of Applied Microbiology ©2021 The Society for Applied Microbiology 7
M. Nguyen and S.G. Joshi Carbapenem resistance and Acinetobacter
widely employed against Gram-negative and Gram-
positive bacteria in hospital environments to disrupt cell
membrane are actively being removed by A. baumannii.
Acinetobacter chlorhexidine (AceI) efflux protein allows
this pathogen to survive under stressful conditions as it
pumps chlorhexidine out of the cell. More studies are
required in order to understand the process behind desic-
cation resistance as well as other environmental persis-
tence of A. baumannii and the role it plays in A.
baumannii virulence (Harding et al. 2017).
Biofilm formation
The biofilm forming capabilities of A. baumannii on
non-living and biologic surfaces (medical devices and
host tissues) allow it to resist antibiotic agents, which
subsequently creates a problem for infection control
(Greene et al. 2016). Biofilm formation is initiated and
maintained by a type I chaperone-usher pilus system
called Csu pil, and by a biofilm-associated protein (Bap),
modulated by the BfmRS two-part regulatory complex.
GacSA is another two-component system that is associ-
ated with controlling the appearance of the Csu gene and
as a result with the formation of biofilm. For soft tissue
and skin-related diseases, A. baumannii creates biofilms
in the wound and on occlusive dressing (Harding et al.
2017). The formation of biofilm especially gives rise to
medical-device-related infections as seen in a multicentre
cohort study where all urinary or bloodstream infections
related to the catheter due to A. baumannii were pro-
duced by biofilm-forming strains (Lin and Lan 2014).
Under inhospitable environmental conditions, A. bau-
mannii cells in the biofilm can become dormant and
metabolically inactive, which allows it to survive under
environmental stress (Greene et al. 2016).
Other virulence factors
Proteins, such as the OMP-A of A. baumannii (AbOmpA,
previously Omp38), are important in infections caused
by A. baumannii, as seen in in-vitro and animal studies
(Dijkshoorn et al. 2007). AbOmpA has been associated
with host epithelial cell death through mitochondrial tar-
geting and appears to be a key component of the patho-
gen’s increased degree of intrinsic resistance to a variety
of antibiotics. Processes related to iron acquisition and
human serum resistance are equally important for the
pathogen’s survival during bloodstream infections (Dijk-
shoorn et al. 2007).
Bacterial motility is also related to the pathogen’s
disease-causing attributes. A. baumannii strains have two
different modes of movement: twitching and surface
motility. Acinetobacter baumannii surface-associated
motility currently depends on production of
1,3-diaminopropane (DAP), quorum sensing and lipo-
oligosaccharide production, whereas twitching motility
depends on pili (type IV) for forward movement by
retraction and extension (Harding et al. 2017). Analysing
A. baumannii stress-response mechanisms leads to a bet-
ter understanding of its ability to adapt to harsh environ-
mental conditions and its success at thriving under
nosocomial conditions as compared to other hospital-
acquired infectious members.
Clinical importance of Acinetobacter baumannii
Nosocomial infections
The Infectious Diseases Society of America described A.
baumannii as one of the greatest nosocomial micro-
organisms ever since its arising clinical importance in the
1980s and its increasing ability for nosocomial spread
(Nowak and Paluchowska 2016). Once the A. baumannii
is found in a hospital surroundings, there is a serious
amount of health risk for vulnerable, chronically ill
patients in ICU wards since most of them are immuno-
compromised and stay in the hospital for an extended
period of time (Howard et al. 2012). Acinetobacter bau-
mannii is responsible for a number of diseases such as
pneumonia (especially VAP), osteomyelitis, peritonitis,
endocarditis, septicaemia, meningitis, and wound, skin,
soft tissue, urinary tract, ear and eye infections (Joshi
et al. 2006; Lima et al. 2019).
Risk factors for A. baumannii infection comprise of
prematurity in newborns, coexistence of significant
underlying conditions, advanced age, immune suppres-
sion, major trauma (in particular, burns), major surgery
or number of invasive procedures, mechanical ventilation,
presence of indwelling devices (such as intravascular and
urinary catheters, drainage tubes), previous or extended
stay in ICU or hospital, and previous dialysis or prescrip-
tion of antimicrobial therapy in the last 90 days. Simi-
larly, risk factors for acquisition of MDR A. baumannii
strain also consist of lengthy mechanical ventilation,
longer ICU or hospital stay, vulnerability to infected
patients, increased seriousness of disease and administra-
tion of broad-spectrum antibiotics, specifically third-
generation cephalosporins, fluoroquinolones and car-
bapenems (Dijkshoorn et al. 2007; Howard et al. 2012;
Vaze et al. 2013; Pogue et al. 2014).
As of 2018, A. baumannii infections make up approxi-
mately 2% of all healthcare-related infections in the Uni-
ted States and Europe, and about double the percentage
in Asia and the Middle East (Harding et al. 2017). Even
though other Gram-negative pathogens may have a
higher rate of infection compared to A. baumannii, about
45% of all A. baumannii isolates are considered to be
MDR, which is quadruple the rate seen in other Gram-
negative pathogens such as P.aeruginosa and Klebsiella
Journal of Applied Microbiology ©2021 The Society for Applied Microbiology8
Carbapenem resistance and Acinetobacter M. Nguyen and S.G. Joshi
pneumoniae, and the rates can be as high as 70% in Latin
America and the Middle East (Harding et al. 2017). In
addition, the probability of mortality may surge from 8
to 40% with nosocomial A. baumannii infections (Nowak
and Paluchowska 2016). As a result of the increasing
prevalence of MDR A. baumannii infections worldwide,
the Center for Disease Control and Prevention (CDC)
considers MDR Acinetobacter species a significant menace
to human health. CRAB is also a global and critical prior-
ity according to the World Health Organization (WHO)
(Harding et al. 2017; Wong et al. 2019). Therefore, the
need for novel treatments against A. baumannii and fre-
quent monitoring and prevention activities are a top pri-
ority.
Community-acquired infections
In addition, A. baumannii can cause, although less fre-
quently, community-acquired infections, such as bacter-
aemia and pneumonia with the latter making up 85% of
A. baumannii community-acquired infections (Antunes
et al. 2014). Risk factors include gender (males are more
affected) and underlying conditions, such as alcoholism,
smoking, chronic obstructive pulmonary disease and dia-
betes mellitus (Dijkshoorn et al. 2007). Community-
acquired A. baumannii pneumonia is also more severe
than nosocomial pneumonia since it is fulminant with
mortality occurring within 8 days of diagnosis and has a
very high mortality rate (Telang et al. 2011; Antunes
et al. 2014). Other presentations of community-acquired
A. baumannii infections are rare.
Carbapenem resistance in Acinetobacter
baumannii
Acinetobacter baumannii is an important nosocomial
pathogen, especially in ICUs for its involvement in criti-
cal healthcare associated diseases and infections. For the
last-resort treatment of A. baumannii infections (includ-
ing MDR A.baumannii infections), healthcare providers
have resorted to carbapenems. Unfortunately, ever since
the first A. baumannii that showed resistance to car-
bapenem was identified in 1991, there is a global rise in
the amount of A. baumannii strains that have acquired
resistance to these antimicrobial drugs (Tal-Jasper et al.
2016; Lima et al. 2019). Hospitals in North America
experienced a rise in resistance rates in A. baumannii,
from 10% in 2003 to 580% in 2008 and data taken
from European Antimicrobial Resistance Surveillance
Network (EARS-Net) indicate that carbapenem-resistant
Acinetobacter species significantly threatens public health
in Europe, especially in Southern and Eastern Europe
where more than 70% of all invasive Acinetobacter species
isolates were non-susceptible to carbapenems (Lima et al.
2019; Ayobami et al. 2020). A rapid rise and development
of CRAB is seen in South and Southeast Asia, with a
greater than 50% rate of carbapenem resistance for A.
baumannii in most hospitals, especially in ICU settings
(Hsu et al. 2017). The mechanisms that render A. bau-
mannii resistant to carbapenem threaten the efficacy of
carbapenems.
Mechanisms of carbapenem resistance in Acinetobacter
baumannii
The mechanisms of carbapenem resistance in A. bauman-
nii can be typically sorted into four groups:
Alterations in penicillin-binding proteins
Carbapenem resistance mechanism among A. baumannii
strains is associated with decreased drug affinity due to
downregulation of PBPs (Almasaudi 2018). For example,
the lack of 732-kDa PBP in A. baumannii isolates with
imipenem minimum inhibitory concentrations (MICs) of
greater than 4 mg l
1
was related to carbapenem resis-
tance in addition to production of carbapenemases
(Poirel and Nordmann 2006). Even though mutations
modifying the production level or the binding affinity of
PBPs lead to resistance in b-lactam antimicrobials, PBP’s
role is associated with only low-level carbapenem resis-
tance in A. baumannii (Nowak and Paluchowska 2016;
Nordmann and Poirel 2019).
Loss of outer membrane porins
Another carbapenem resistance mechanism in Acinetobac-
ter species is related to membrane impermeability due to
the reduced expression or mutation in porins. Porin
channels and OMPs are normally responsible for the
transport of antimicrobial agents into the cell (Man-
chanda et al. 2010; D’Souza et al. 2019). There are several
OMPs that are associated with transporting b-lactams
across A. baumannii membrane and therefore car-
bapenem non-susceptibility, such as 29-kDa protein
(CarO or carbapenem-associated OMP), HMP-AB and
OmpW (Hsu et al. 2017; Wong et al. 2019). A decrease
in the expression of CarO, for example, leads to
decreased susceptibility to imipenem and meropenem
(Sen and Joshi 2015; Nowak and Paluchowska 2016;
Almasaudi 2018). Further studies will be helpful in
affirming a direct correlation between existence or
absence of these porin proteins and carbapenem respon-
siveness (Wong et al. 2019).
Overexpression of efflux pumps
Efflux pumps (EP) can also play a part in carbapenem
susceptibility in A.baumannii (Wong et al. 2019). Com-
pared to outer membrane porins which are associated
Journal of Applied Microbiology ©2021 The Society for Applied Microbiology 9
M. Nguyen and S.G. Joshi Carbapenem resistance and Acinetobacter
with antibiotic uptake, efflux systems are responsible for
actively removing a number of antimicrobial agents by
pumping them out of the cell which leads to multidrug
resistance (Gordon and Wareham 2009; Manchanda et al.
2010; Wong et al. 2019). There are five EP families that
show an increase in bacterial resistance, but mainly three
of them can be found in the pathogen: multidrug and
toxic compound extrusion (MATE) family, the major
facilitator superfamily (MFS) and the resistance-
nodulation-cell division (RND) family (Nowak and Palu-
chowska 2016). AdeABC, AdeFGH and AdeIJK are RND
type efflux pumps that can be found in Acinetobacter spe-
cies and are important in contributing susceptibility
towards carbapenem (Zhu et al. 2020). The structure of
the RND family typically includes a transporter protein
found in the inner membrane, a membrane fusion pro-
tein (MFP) and an OMP channel. The adeABC gene pro-
duct has the strongest association with carbapenem
resistance and is made up of three components: AdeA
(MFP), AdeB (transporter protein) and AdeC (OMP).
The expression of adeABC is normally managed by a
response regulator, adeR and a sensor kinase, adeS. Over-
expression of AdeABC efflux pump contributes to high-
level carbapenem resistance when combined with
carbapenem-hydrolysing oxacillinases (OXAs) (Sen and
Joshi 2015; Nowak and Paluchowska 2016; Almasaudi
2018; Zhu et al. 2020).
Synthesis of carbapenem-hydrolysing b-lactamases
(carbapenemases)
Inactivation or enzymatic degradation of carbapenems is
the most significant carbapenem resistance mechanism in
A. baumannii and is usually carried out by carbapene-
mase enzymes, which are found usually on plasmids and
are very transmissible (Nordmann and Poirel 2019;
Bansal et al. 2020).
There are four main molecular b-lactamase enzyme
categories detected in A. baumannii according to their
catalytic domain and substrate preference: classes A, B, C
and D (from Ambler classification system). Carbapene-
mases are from Class A, B and D, while cephalosporins
are hydrolysed by class C enzymes. Metallo-b-lactamases
(MBLs) or b-lactamases found in class B need a water
molecule and a zinc ion (a divalent cation) to trigger and
disrupt the b-lactam ring. On the other hand,
b-lactamases from class A, C and D are non-metallo-
carbapenemases that require serine for their catalytic
activity (Nowak and Paluchowska 2016; Abouelfetouh
et al. 2019; Nordmann and Poirel 2019). Examples of car-
bapenemases that are clinically relevant and occur among
A. baumannii include K. pneumoniae carbapenemases
(KPC) and Guiana extended-spectrum b-lactamase (GES)
from class A; imipenemase (IMP), Verona integron-
encoded metallo-b-lactamase (VIM), Seoul imipenemase
(SIM) and New Delhi metallo-b-lactamase (NDM) from
class B. These are summarized in Fig. 5 (Nowak and
Paluchowska 2016). MBLs and carbapenemases (more
precisely OXA-type) exhibit similar phenotypic resistance.
OXA-type carbapenemases are more commonly seen in
A. baumannii than MBLs but the latter demonstrate
carbapenem-resistant hydrolytic activities that are 100–
1000 times deadlier than that of OXA-type carbapene-
mases (Peleg et al. 2008; D’Souza et al. 2019).
Carbapenem-hydrolysing class D b-lactamases
(CHDLs) or OXA hydrolyse isoxazolylpenicillin and are
the most frequent cause of rendering A. baumannii resis-
tant to carbapenem (Nowak and Paluchowska 2016).
When A. baumannii acquires these particular OXA-group
b-lactamase genes that confer resistance and are trans-
ported by plasmids or other motile genetic components,
there is a rapid spread of many multiple carbapenem
resistance genes in this pathogen. These genes are dupli-
cated in an independent manner and exchanged between
bacterial cells and species. Plasmids are therefore crucial
for the quick transmission of carbapenem resistance
(Raible et al. 2017; Hamidian and Nigro 2019).
There are six main groups in CHDLs: the intrinsic
OXA-51-like and the acquired OXA-23-like, OXA-58-like,
OXA-24/40-like, OXA-235-like and OXA-143-like
b-lactamases (Nowak and Paluchowska 2016; Abouelfe-
touh et al. 2019). CHDLs are associated with upstream
insertion elements which lead to overexpression of
Class A
GES KPC SIM IMP
Class B Class D
OXA-23-
like group
OXA-
40/24-like
group
OXA-48-
like group
OXA-51-
like group
OXA-58-
like group
OXA-143-
like group
NDM VIM
Carbapenemases
Figure 5 Examples of carbapenemases that are clinically relevant and occur among Acinetobacter baumannii (adapted from Nowak et al. 2016).
Journal of Applied Microbiology ©2021 The Society for Applied Microbiology10
Carbapenem resistance and Acinetobacter M. Nguyen and S.G. Joshi
OXA-type carbapenemases and subsequent carbapenem
resistance (D’Souza et al. 2019). In the mid-1980s in Scot-
land (UK), OXA-23 was recognized as the earliest CHDL-
encoding gene in A. baumannii; it includes subgroups
OXA-27 and OXA-49 and spreads via plasmid-mediated
transfer (Pogue et al. 2014). The ISs that are associated
with the expression of OXA-23 are found upstream from
bla
OXA23
and are known as ISAba1 or ISAba4 (Sen and
Joshi 2015; Ramirez et al. 2020). OXA-23 can be predomi-
nantly found in clinical A. baumannii isolates from the
United States, India and South Korea (Ramirez et al.
2020). Comparable to bla
OXA23
, genes that encode
bla
OXA58
also spread through plasmid-mediated transfer
but were first identified in USA military personnel return-
ing from Iraq while sustaining traumatic combat injuries
(Pogue et al. 2014). IS elements, ISAba 1, ISAba 2, ISAba
3 and IS 18, are found upstream in A. baumannii isolates
retaining bla
OXA58
indicating contribution to expression of
OXA-58. OXA-58-like enzymes can be mainly found in A.
baumannii isolates from the United States, Spain and
Thailand (Ramirez et al. 2020). Unlike bla
OXA23
and
bla
OXA58
, genes related to the bla
OXA24
cluster seem to
only be located on chromosome, not on plasmids and are
mostly found in the United States and Spain (Pogue et al.
2014; Ramirez et al. 2020). OXA-51-group carbapene-
mases are usually expressed at low levels and expression of
these enzymes also requires insertion of ISAba 1 upstream
of the structural gene (Manchanda et al. 2010; Pogue
et al. 2014; Sen and Joshi 2015). OXA-51-like enzymes
can hydrolyse imipenem or meropenem but its hyperpro-
duction appears to confer different degrees of carbapenem
susceptibility in the pathogen. OXA-51 enzymes are
detected in all A. baumannii isolates but they are mainly
distributed in Germany, Brazil and Japan (Pogue et al.
2014; Ramirez et al. 2020).
Among the OXA-group b-lactamase genes mentioned
above, overexpression of OXA-23 is the most wide-
spread mechanism of carbapenem resistance in A. bau-
mannii isolates (Ramirez et al. 2020). In North America,
specific carbapenemases including OXA-23 and other
OXA-type carbapenemases (e.g. OXA-40 and OXA-58)
are considered the most frequent mechanism of car-
bapenem resistance in Acinetobacter species. In India
and surrounding countries in Asia-Pacific, carbapene-
mase enzyme OXA-23 is also a frequent mechanism of
resistance A. baumannii. When compared with North
America, Asia-Pacific and Europe, there is a broad range
of mechanisms present in A. baumannii strains found in
Latin America: the most common mechanism being
OXA enzymes such as OXA-23, OXA-58, OXA-72,
OXA-143 and OXA-253 but there is also detection of
NDM-1, VIM-1, IMP-1 and IMP-10 (Nordmann and
Poirel 2019).
A wide variety of mechanisms can cause carbapenem
susceptibility but enzymatic mechanisms especially the
existence of MBLs and CHDLs and acquisition of
carbapenemase-coding genes are the strongest mecha-
nisms among A. baumannii isolates (Abouelfetouh et al.
2019; Ramirez et al. 2020). Overall, identification of car-
bapenemases among resistant strains is extremely impor-
tant for choosing the right treatment protocol and for
limiting the advancement of carbapenem-resistant strains
among A. baumannii isolates.
Genetics of resistance in Acinetobacter baumannii
As mentioned above, genes that encode carbapenemase is
transported within A. baumannii genome on chromo-
somes or plasmids but mobile genetic components, such
as IS, integrons, resistance islands (RI), are an important
part of resistance methods found in carbapenemases
(Nowak and Paluchowska 2016).
Insertion sequences
The smallest mobile DNA segment that is important for
carbapenem resistance through genome rearrangements
and insertion mutations is IS. It specifically works by
containing promoter regions that give rise to overex-
pressed downstream resistance determinants. There are
about 30 different types of IS in A. baumannii but the
most widely distributed in this pathogen and the most
important for carbapenem resistance is ISAba1 because of
its mobilization and expression of OXA-type carbapene-
mases (Mugnier et al. 2009; Nowak and Paluchowska
2016). For example, ISAba1 found upstream of bla
OXA23
,
bla
OXA58
,and bla
OXA51
genes provides the gene promoter
that may lead to carbapenem resistance. ISAba1 is unique
to A. baumannii but the presence of other IS elements is
equally important for decreased susceptibility to other
antibiotics in A. baumannii (Peleg et al. 2008). Overall, IS
amplifies the growth of resistance and spread of virulence
determinants within A. baumannii (Mugnier et al. 2009).
Integrons
In contrast to OXA-type carbapenemases, MBLs generally
appear in integrons. These are able to acquire antibiotic
resistance determinants and promote their transcription
and expression. During isolation, integrons are immobile
and are thus implanted inside plasmids or transposons;
these behave like vehicles that spread resistance. Among
the classes of integrons, those from class 1 are the most
typical among A. baumannii strains globally. For example,
the genetic determinants of IMP, VIM and SIM-type
enzymes were discovered on class 1 integrons of A. bau-
mannii (Peleg et al. 2008; Nowak and Paluchowska
2016). The clinical significance of integrons is that the
Journal of Applied Microbiology ©2021 The Society for Applied Microbiology 11
M. Nguyen and S.G. Joshi Carbapenem resistance and Acinetobacter
excessive use of a single antimicrobial drug can promote
overexpression of many resistance determinants due to
one common promoter. In general, A. baumannii strains
that carry these integrons are significantly more drug
resistant than strains without integrons (Peleg et al.
2008).
Resistance Islands
Resistance islands can also render A. baumannii resistant
to carbapenem. They are another mobile genetic element
that are described as a specific region that can harbour
multiple horizontally transferred antimicrobial resistance
determinants (Sung et al. 2012; Nowak and Paluchowska
2016). A few A. baumannii resistance islands (AbaR) have
already been fully characterized including, AbaR1, AbaR3,
AbaR4, AbaR5-Aba19 and AbaR25. In 2006, the earliest
AbaR was found in MDR AYE strain and is known as
AbaR1 (Nowak and Paluchowska 2016). It harbours a
cluster of 45 resistance genes, including bla
OXA69
which is
a member of the bla
OXA51-like
group and makes it resis-
tant to aminoglycosides, aminocyclitols, chloramphenicol
and tetracycline (Sung et al. 2012; Nowak and Palu-
chowska 2016). AbaR25 (a variant of AbaR4) is associ-
ated with CRAB isolates in Latvia. Studies concerning
these isolates showed the presence of AbaR25 that carried
bla
OXA-23-like
genes in A. baumannii (Nowak and Palu-
chowska 2016). Overall, research has shown that MDR A.
baumannii strains can acquire their antimicrobial resis-
tant traits via IS, integrons and RIs. This unique ability
makes A. baumannii a problematic nosocomial pathogen
and makes it one of the most serious threats to hospital-
ized patients.
Other types of gene transfer
Acinetobacter species are considered suitable for genetic
exchange and can easily acquire foreign genetic material,
particularly antibiotic resistance genes (Almasaudi 2018).
Other methods of horizontal gene transfer among A. bau-
mannii include transferring DNA to recipient cell in a
process called transformation, direct cell to cell transfer
through conjugative plasmids or conjugation and trans-
duction or phage-assisted transfer (Silva and Domingues
2016; Almasaudi 2018). Transformation events were first
reported in 1969 in Acinetobacter strain, whereby A.cal-
coaceticus was able to take up DNA from lysed bacterial
cells and recombine this DNA into its own genome (Juni
and Janik 1969). Another method of horizontal gene
transfer that is associated with the development of novel
antibiotic-resistant strains is conjugation. A study
revealed that in vitro conjugation may be responsible for
the transfer of antibiotic resistance genes (e.g. bla
OXA-23
,
bla
OXA-58
) among Acinetobacter species isolates (Leung-
tongkam et al. 2018). Reports indicate that conjugation is
the most prevalent mechanism of carbapenemase deter-
minants acquisition and subsequent spread of antimicro-
bial resistance (Silva and Domingues 2016). Lateral gene
transfer can occur through phage-mediated transduction.
Recent experimental studies show horizontal transfer of a
transposon (Tn125) carrying bla
NDM
genes from a CRAB
strain to a carbapenem-susceptible A. baumannii strain
by means of transduction (Silva and Domingues 2016).
An understanding of the mechanism behind the genetic
exchange of resistance genes in A. baumannii is critical in
preventing the further spread of carbapenem resistance.
Overcoming carbapenem resistance
As mentioned previously, the capabilities of A. baumannii
to persevere in a hospital environment for an extended
amount of time on surfaces as a result of the rapid devel-
opment of acquired mechanisms that render it resistant
to antibiotics makes it a troublesome pathogen in hospi-
tals, especially in ICUs. To prevent these MDR Acineto-
bacter species from further disseminating, there is a
pressing need to develop and enforce control strategies
for dealing with A. baumannii and alleviating increased
resistance in ICUs. These essential control measures are
summarized in Fig. 6 and will be further discussed in the
sections below (Silva and Domingues 2016).
Strategies for intervention and prevention
A multifaceted programme in hospitals can be imple-
mented to decrease the frequency and chance of out-
breaks including endemic situations. Outbreaks can
be potentially controlled by adopting an infection con-
trol programme, taking surveillance cultures, and imple-
menting an antimicrobial stewardship programme
(Valencia-Mart
ın et al. 2019).
Infection control precautions: environmental
decontamination, hand hygiene and cohorting
In order to effectively control MDR A. baumannii out-
breaks, hospitals should implement rigorous disinfection
and environmental cleaning policies. ICU wards should
be periodically closed several times a year for terminal
cleaning or temporarily closed when the ward is affected
in order to terminate an outbreak. Every time a colonized
patient is discharged, all bedside of the ICU and the
rooms in other adjacent wards should also be terminally
cleaned (Garnacho-Montero et al. 2015; Valencia-Mart
ın
et al. 2019). Hypochlorite-based disinfectants (at least
05% concentration) may be used for decontamination of
non-disposable medical products (Garnacho-Montero
et al. 2015). For effective disinfection of medical equip-
ment that are contaminated with A. baumannii, hospitals
Journal of Applied Microbiology ©2021 The Society for Applied Microbiology12
Carbapenem resistance and Acinetobacter M. Nguyen and S.G. Joshi
may utilize ethylene oxide or H
2
O
2
free radicals (Pogue
et al. 2014). Each infected patient should have their own
exclusive medical products and disposable medical prod-
ucts should be discarded as soon as the patient does not
need them anymore while non-disposable products
should be disinfected. Environmental cleaning and medi-
cal equipment disinfection can be carefully monitored by
novel equipment such as fluorescent dye and ATP biolu-
minescence. Infection control team should meet on a reg-
ular basis with the cleaning staff for educational purposes
and feedback of the results (Garnacho-Montero et al.
2015; Valencia-Mart
ın et al. 2019). Despite terminal
cleaning, it is still difficult to completely eradicate A. bau-
mannii from the environment (Weinberg et al. 2020).
Studies show that patients have at least a 39% risk of
acquiring nosocomial infection when they take over a
room that was previously occupied by an MDR
pathogen-infected patient (Feng et al. 2020). This phe-
nomenon may be associated with genes, such as gene
qacE and qacED1that have become resistant to disinfec-
tants (Weinberg et al. 2020). In order to make up for the
shortfall in manual cleaning, aerosolized or vapourized
hydrogen peroxide, continuous/pulsed UV-C light and
other touchless methods may be proposed in addition to
normal cleaning practices (Weinberg et al. 2020).
Hand hygiene compliance is extremely important since
hands of healthcare workers are the most common mode
of transmission (Lynch et al. 2017). In addition, 20–40%
of nosocomial infections may be attributed to cross-
transmission of A. baumannii which can occur when
there is direct contact from hands and gloves from
healthcare providers to patients (Weinberg et al. 2020). A
hand-cleansing agent that is made up of 10% povidone-
iodine and 70% ethyl alcohol demonstrates effectiveness
for eradicating A. baumannii hospital strains (Weinberg
et al. 2020). In addition, hand hygiene educational ses-
sions or courses and feedback on hand hygiene compli-
ance and colonization/infection rates should be
continuously provided to all personnel (physicians,
nurses, other workers) in order to stress the importance
of hand hygiene for controlling MDR A. baumannii out-
breaks in the hospital (Ben-Chetrit et al. 2018; Valencia-
Mart
ın et al. 2019; Weinberg et al. 2020). In addition to
standard precautions that include washing hands pre-
and post-patient care, contact precaution measures to
interrupt transmission which include the use of dispos-
able gowns and gloves for barrier precautions should be
included in routine infection control measures (Enfield
et al. 2014; Liu et al. 2014). For healthcare workers with
greater exposure to MDR A. baumannii such as those
working in burn units, plastic aprons may also be used as
protective clothing to decrease the chances of contamina-
tion (Weinberg et al. 2020). Skin disinfection with
chlorhexidine or daily bathing with chlorhexidine
gluconate-impregnated clothes can also be used for pre-
vention of the spread of this pathogen (Metan et al.
2019).
Patient and healthcare personnel cohort isolation is
another component of an effective strategic intervention
to limit the outbreaks of infection. Single rooms with its
own equipment (e.g. portable X-ray machine) should be
used with its own dedicated staff; however, if this is not
possible, patients who harbour the same organisms
should be grouped together (Enfield et al. 2014;
Genotyping and
rapid diagnostics
Antimicrobial
Stewardship
Program (ASP)
Surveillence
cultures:
Infection control
measures:
Environmental
decontamination
Hand hygiene
Cohorting
Intervention &
prevention strategies
to overcome
carbapenem
resistance in A.
baumannii in
hospitals
Patient
Environment
•
••
•
•
Figure 6 Important infection control measures that can be adopted to prevent Acinetobacter baumannii from further disseminating (adapted
from Garnacho-Montero et al. 2015).
Journal of Applied Microbiology ©2021 The Society for Applied Microbiology 13
M. Nguyen and S.G. Joshi Carbapenem resistance and Acinetobacter
Garnacho-Montero et al. 2015). These units should be
closed to non-infected and non-colonized patients (Mon-
tefour et al. 2008). Grouping staff that solely interact with
infected patients may decrease stress among other hospi-
tal workers and administration (Garnacho-Montero et al.
2015).
Surveillance cultures: patient and environmental cultures,
rapid diagnostics
Active A. baumannii culture surveillance of patients for
colonization can also help reduce the rate of nosocomial
infections. If patients are suspected of being a part of an
outbreak or have a higher chance of transmitting the
strain, cultures should be drawn from different sites such
as nose, throat, skin sites (axilla and/or groin), rectum,
open wounds and endotracheal aspirates. One site culture
has low sensitivity (13–29%), but six site cultures increase
sensitivity to 50% (Garnacho-Montero et al. 2015).
Results should then be communicated quickly and effec-
tively to actively carry out the appropriate infection con-
trol course of action. The surfaces from a hospital
environment (wall surfaces and water supplies) can also
be sampled whenever there is the chance that the source
of an outbreak situation is found in an inert environment
(Montefour et al. 2008). As seen in Table 1, potential
hospital environment sources of A. baumannii include
supplies (carts, protective masks), invasive equipment
(catheters), parts of the room (blood pressure cuffs, door
handles, bed rails, linens, mattresses, pillows, sinks), ven-
tilatory or respiratory equipment, air conditioners, infu-
sion pumps and liquids (blood products, enteral
formulas, saline, soap, distilled water, humidifier water or
non-sterile water) (Montefour et al. 2008).
The rapid detection of CRAB strain is important for
decreasing time to therapy and preventing outbreaks.
Identifying Acinetobacter sp. to a species level and differ-
entiating A. baumannii group from Acinetobacter sp. that
do not belong in A. baumannii group is a crucial part of
controlling outbreak (Garnacho-Montero et al. 2015). In
order to obtain accurate susceptibility test results which
would provide healthcare providers with appropriate
therapeutic options in a timely manner, rapid diagnostic
tests should be considered alongside surveillance cultures
of patients (Doi 2019).
In order to quickly detect MDR A. baumannii, chro-
mogenic media can be used, such as CHROMagar
TM
Acinetobacter (CHROMagar; Paris, France), which is a
selective agar plate containing chromogenic substrate and
agents that prevent a majority of Gram-positive organ-
isms and carbapenem-susceptible Gram-negative bacilli
from flourishing (Abbott et al. 2014; Garnacho-Montero
et al. 2015). With the use of peri-anal swabs and sputum,
these chromogenic media are capable of detecting all A.
baumannii and its MDR isolates (Garnacho-Montero
et al. 2015). Another way to properly identify organisms
is the use of genotyping or molecular typing systems of
A. baumannii isolates (Mahamat et al. 2016). It is a fast
identification method that can be used to evaluate and
define the extent of the outbreak by determining strain
relatedness and following transmission pathways (Abbott
et al. 2014; Doi et al. 2015; Garnacho-Montero et al.
2015). Repetitive sequence-based polymerase chain reac-
tion (PCR) and broad range PCR/electrospray ionization
mass spectrometry are examples of molecular typing sys-
tem that are semi-automated with rapid results (turn-
around time of approximately 6 h) (Abbott et al. 2014).
Table 1 Examples of environmental contamination of hospital items (adopted from Montefour et al. 2006)
Room Equipment Liquids Supplies
•Door handle
•Sink
•Tabletop
•Washbasin
•Pillow
•Foam mattress and mattress
with pneumatic pump
•Linen
•Bed rail
•Bedside
•Table
•Blood pressure cuff
•Intravenous stand
•Paper towel dispenser
•Container for sharp objects
Mechanical:
•Monitor, computer and other
machine panel
•Ventilator and other respiratory
equipment
•Air conditioner
•Machine for haemodialysis
•Infusion pump
Invasive:
•Catheter
•Multidose vial for medication injection
Soaps and detergent
Distilled and non-sterile water
Enteral formula
Saline
Blood product
Shared equipment
Protective mask
Crash cart
Trolley
Weighing hammock
Journal of Applied Microbiology ©2021 The Society for Applied Microbiology14
Carbapenem resistance and Acinetobacter M. Nguyen and S.G. Joshi
These methods can help with better understanding of
how the pathogen spreads and how it can be contained
(Garnacho-Montero et al. 2015).
Another technique that has been used for organism
identification and to quickly differentiate between differ-
ent Acinetobacter species, such as A. baumannii from A.
pittii and A.nosocomialis is MALDI-TOF mass spectrom-
etry (MS) systems. MALDI-TOF MS technique is more
efficient for species differentiation than phenotypic sys-
tems and can quickly and reliably discern those that pro-
duce carbapenemase by incubating bacteria with
imipenem for up to 4 h before mixture analysis (Abbott
et al. 2014). Observation of the absence or appearance of
imipenem peaks is then useful for evaluation of A. bau-
mannii clinical isolates and differentiation between iso-
lates with and without a carbapenemase (Kempf et al.
2012a). Over the last few years, studies have shown that
MALDI-TOF MS systems demonstrate precise discern-
ment of A. baumannii species (Garnacho-Montero et al.
2015). The process for Acinetobacter sp. identification to
a genus level is relatively uncomplicated in clinical labo-
ratories; however, other molecular methods are still being
investigated and developed for Acinetobacter species
recognition.
In addition to A. baumannii organism detection, car-
bapenemase detection is equally important for choosing a
therapeutic strategy in a timely manner. Methods used to
detect the presence of a carbapenemase include modified
Hodge test (phenotypic technique), Double-Disk Synergy
Tests or Carba NP test (phenotypic test) (Abbott et al.
2014; Litake et al. 2015; Doi 2019). It is important to
note that phenotypic techniques usually do not differenti-
ate carbapenemase classes and would be more useful
when a particular carbapenemase is known to predomi-
nate (Abbott et al. 2014; Doi 2019). Instead, molecular
techniques such as gene-specific PCR-based techniques,
multiplex PCR or microarray techniques are the gold
standard for carbapenemase detection (Abbott et al.
2014).
Reliable methods of antibiotic susceptibility testing are
equally important for management of infection control
and for giving healthcare providers information on thera-
peutic options to treat their patients. These methods
include but are not limited to broth microdilution,
MicroScan and Vitek 2 systems. Unfortunately, the lack of
international consensus for Acinetobacter species associated
with carbapenem susceptibility breakpoints may negatively
affect the results of testing (Abbott et al.2014).Break-
points recognized by Clinical and Laboratory Standards
Institute (CLSI) may be different than that of the US
FDA, Center for Drug Evaluation and Research (CDER)
or the European Committee on Antimicrobial Susceptibil-
ity Testing (EUCAST) (Humphries et al.2019).
Testing methods mentioned above are either take a
long time (such as modified carbapenem inactivation
method, mCIM, which requires 24 h to detection), con-
sidered expensive (MALDI-TOF MS), or require sub-
stances with limited shelf-life (Carba NP is stored in
solution at 4–8°C for up to 3 days) (Jing et al. 2019). If
detection of carbapenemase strains can help prevent out-
breaks of and treat A. baumannii infections, then rapid
organism and carbapenemase detection method is recom-
mended and should be further investigated. Current
strategies that have been recently developed include
bioluminescence-based carbapenem susceptibility detec-
tion assay (BCDA), an accurate phenotypic method that
allows detection of carbapenem-resistant species in 25h
from culture media (van Almsick et al. 2018), multiplex
real-time PCR to detect and distinguish the most com-
mon carbapenemases present in A. baumannii (OXA-23-
like, OXA-24-like and OXA-58-like subfamilies) in
70 min even when more than one is simultaneously pre-
sent (Mentasti et al. 2020), RevogeneâCarba C assay
which is another a real-time PCR-based assay for the
detection of genes that encode carbapenemases such as
NDM, VIM, IMP, KPC and OXA-48 like) from various
Gram-negative pathogens with a run time of about
70 min (Sadek et al. 2020); fluorescence identification of
b-lactamase activity (FIBA) to detect carbapenemase pro-
duction in bacteria in 10 min (Feng et al. 2020) or auto-
mated BD Phoenix CPO detect test (BD-CPO test) for
the simultaneous detection and Ambler classification of
carbapenemases in Enterobacteriaceae, P.aeruginosa and
A. baumannii complex (results are accessible in 18 h
from cultured bacterial growth) (Saad Albichr et al.
2020).
Overall, further research and development of novel
ways for quick and precise identification of A. baumannii
or carbapenemase is crucial for curbing the dissemination
of carbapenem-resistant strains within healthcare settings
and for providing clinicians and infection control special-
ists quick results so that they can provide patients with a
suitable treatment plan (Mentasti et al. 2020).
Antimicrobial stewardship programme
The implementation of antimicrobial stewardship pro-
gramme (Tal-Jasper et al.) in hospitals and the commu-
nity is associated with reduced incidence of infections,
slowed development of resistance and colonization of
MDR A. baumannii, increased appropriateness of antibi-
otic utilization, and improved treatment rates. ASP is
described as a ‘coherent set of actions which promote
using antimicrobials responsibly’ and is a key part of a
multifaceted plan (policies, antibiotic guidelines, con-
sumption surveillance, continuous education) for the pre-
vention of antimicrobial resistance emergence
Journal of Applied Microbiology ©2021 The Society for Applied Microbiology 15
M. Nguyen and S.G. Joshi Carbapenem resistance and Acinetobacter
(Apisarnthanarak 2012; Dyar et al. 2017; Timsit et al.
2019). An effective ASP usually includes the following
three components: the placement of antibiotic policy,
education regarding the stewardship programme and pro-
gramme monitoring (Manchanda et al. 2010). ASP
requires an evidence-based approach, a coherent state-
ment describing goals and target, a strong system that
collects data which allows prescribers to receive feedback,
and a plan to discern areas that could be improved. For
implementation of ASP, one ICU staff member with
knowledge of antimicrobial therapy is usually appointed
as the leader (Timsit et al. 2019).
Ways that intervention can be used in ASP include the
following: restrictive method in order to regulate inap-
propriate or unnecessary antimicrobial use, such as limit-
ing the use of certain medications (this is usually
approved by an external infectious disease specialist or an
expert in the ICU team); method to increase good beha-
viour opportunities, such as educating prescribers on the
proper use of antimicrobial therapy or implementing
treatment guidelines; and lastly structural method which
can involve computerized antibiotic decision support sys-
tems, rapid antimicrobial resistance diagnostic methods,
surveillance system for the consumption of antibiotics,
ICU leadership and staff involvement, daily interactions
between ICU staff, pharmacists, infection control units
and microbiologists (Dyar et al. 2017; Timsit et al. 2019).
Other elements of antibiotic stewardship are implementa-
tion of a prior approval programme, the practice of
streamlining (switching from broad-spectrum therapy to
one that is narrower as soon as the results for susceptibil-
ity testing results are available) and lastly antibiotic
cycling (Rebmann and Rosenbaum 2011). The latter
involves regular rotation of two or more classes of for-
mulary drugs in order to prevent bacteria from having
enough time to become resistant as well as careful obser-
vation of resistance data to prematurely detect any
unwanted trends. The use of antibiotic cycling to decrease
the spread of A. baumannii resistance is still being inves-
tigated.
Strict infection control programmes are important in
inhibiting breakout of infections due to A.baumannii.
Different practices for infection control in hospitals, such
as in-patient care units, are outlined in Table 2 (Doi
et al. 2015). When there is involvement at all levels of
healthcare personnel, infection control programme imple-
mentation will be more effective and successful (Man-
chanda et al. 2010). It may not be efficient to use these
control measurements separately, but a combination of
the infection control measures mentioned above may be
the best option to slow down the development of an
endemic situation (Garnacho-Montero et al. 2015).
Treatment options
For infections that involve Acinetobacter sp., carbapenem
is the most common agent of choice; however, as
carbapenem-resistant strains continue to increase with
decreased susceptibility to carbapenems, there are limita-
tions to its usage as monotherapy especially for critical
infections (Garnacho-Montero et al. 2015). If carbapenem
resistance is suspected, infections can be treated with the
different synergistic activities of a variety of antimicro-
bials (V
azquez-L
opez et al. 2020). It is also important to
consider in vitro antibiotic susceptibility testing when
determining a regimen that includes a combination of
different agents (Kempf and Rolain 2012b). Possible
agents used in therapeutic combinations to treat
carbapenem-resistant A. baumannii infections are
described below.
b-lactamase inhibitors
b-lactamase inhibitors commonly used in CRAB infec-
tions are sulbactam, tazobactam and clavulanic acid;
however, studies indicate that sulbactam is the most
effective among the three and can be recommended as a
Table 2 Examples of infection control measures in hospitals to decrease spread of Acinetobacter baumannii and reduce the emergence of its
resistance (adopted from Manchanda et al. 2010)
On a daily basis During situations of outbreak
•Regular precautions such as hand hygiene compliance
•Patient and environmental surveillance cultures
•Environmental decontamination and disinfection policies
•Contact barrier precautions such as use of disposable gowns and
gloves
•Training programmes and continuous education on infection con-
trol policies and procedures
•ASP implementation and monitoring
•Point source control if source is distinguishable
•Re-enforcement of control measures mentioned above
•Patient and healthcare personnel cohort isolation
•Clinical unit or ward closure (if outbreak cannot be managed by
methods listed on the left)
Journal of Applied Microbiology ©2021 The Society for Applied Microbiology16
Carbapenem resistance and Acinetobacter M. Nguyen and S.G. Joshi
treatment option for MDR A. baumannii infections, espe-
cially pneumonia, blood or other nosocomial infections
(V
azquez-L
opez et al. 2020). Sulbactam is a penicillin
derivative, Amber class A b-lactamase inhibitor with
affinity for PBP-2 of A. baumannii and is usually avail-
able co-formulated with another b-lactam such as ampi-
cillin or cefoperazone (Viehman et al. 2014; D’Souza
et al. 2019). Sulbactam is unaffected by OXA-23 and
other common carbapenemases found in A. baumannii
and has shown to retain activity against CRAB (Peri et al.
2019). It should not be used as monotherapy but in com-
bination with other agents (such as fosfomycin, a pepti-
doglycan biosynthesis inhibitor) (Doi et al. 2015).
Other, more recent b-lactamase inhibitors that are
being investigated include durlobactam (DUR or
ETX2514), which is a diazabicyclooctenone b-lactamase
inhibitor which exhibits comprehensive activity against
Amber class A, C and D b-lactamases (Yang et al. 2020).
DUR works by restoring sulbactam activity against resis-
tant A. baumannii and its inhibition of OXA-type car-
bapenemases makes it a promising therapy to treat MDR
A. baumannii infections. When used in combination with
sulbactam, durlobactam demonstrated efficient potency
against A. baumannii isolates as seen in a broth microdi-
lution study where 246 carbapenem-resistant non-
duplicate A. baumannii strains were investigated (Seifert
et al. 2020). Sulbactam-DUR is currently undergoing clin-
ical development for therapy against infections caused by
A. baumannii (Lickliter et al. 2020).
Polymyxin or colistin
Polymyxin is an amphipathic lipopolypeptide antimicro-
bial that can prompt rapid concentration-dependent bac-
terial killing by interacting with lipid A of Gram-negative
bacterial outer membrane and disrupting the cell mem-
brane, thereby leaking intracellular components and caus-
ing apoptosis (Pogue et al. 2014; Zavascki et al. 2014;
Doi et al. 2015). Polymyxin B is delivered as an active
drug, whereas polymyxin E (colistin) is given intra-
venously as an inactive prodrug colistin methanesulfonate
(CMS) (the latter formulation more commonly in clinic)
(Doi et al. 2015). Although colistin was previously dis-
continued for its high nephrotoxicity, current studies
demonstrate lower nephrotoxicity rates when certain risk
factors are taken into account, such as age, dosage, dura-
tion and coexisting conditions such as obesity, hyperten-
sion or hypoalbuminemia (Asif et al. 2018). Acinetobacter
baumannii infections can be treated with pharmacokineti-
cally optimized doses of colistin as a part of combination
regimen with a second agent, such as carbapenem (dori-
penem, meropenem and imipenem), tigecycline, sulbac-
tam or rifampicin/teicoplanin (Viehman et al. 2014; Doi
et al. 2015; V
azquez-L
opez et al. 2020). It is important to
note that polymyxin resistance may develop in A. bau-
mannii after treatment with CMS. In addition, therapies
involving intravenous CMS show little effectiveness in
central nervous system infections due to colistin’s low
diffusion into the cerebrospinal fluid (Doi et al. 2015).
Tetracyclines
Tetracyclines, such as minocycline and doxycycline, as
well as glycylcyclines, are additional options against car-
bapenem and sulbactam-resistant A. baumannii strains.
Minocycline and doxycycline are especially effective
against VAP produced by these strains and an advantage
of prescribing minocycline to patients as compared to
imipenem, colistin or tigecycline is that it can be taken
via oral route (V
azquez-L
opez et al. 2020). Tigecycline,
which is a glycylcycline derived from minocycline, has
been accepted by the US FDA in 2005 as a bacteriostatic
antibiotic to treat complicated skin and soft tissue infec-
tions and that of intra-abdomen; however, using tigecy-
cline alone to treat infections that are invasive, such as
VAP or bloodstream infections, is not recommended
(Pogue et al. 2014; Zavascki et al. 2014). It works by
inhibiting protein synthesis of bacterial and limiting bac-
terial growth when it binds to the 30S ribosomal subunit,
thereby preventing aminoacyl transfer RNA from entering
the A binding site of ribosome and subsequently prevent-
ing amino-acyl residues from incorporating itself into the
elongation of peptide chains (Zavascki et al. 2014; Doi
et al. 2015). It is more effective to use tigecycline together
with a second agent (such as carbapenem or expanded-
spectrum cephalosporin) rather than using tigecycline by
itself especially for patients with CRAB bloodstream
infections (Doi et al. 2015). Currently, tigecycline can be
used as an alternative treatment of MDR A. baumannii in
patients who have polymyxin intolerance or for
polymyxin-resistant isolates; however, its role in combi-
nation with other antimicrobials for the treatment of
CRAB is still under investigation (Zavascki et al. 2014;
Peri et al. 2019).
Other therapeutic options
Another option for the treatment of A. baumannii infec-
tions is the combination of trimethoprim (TMP)–sul-
famethoxazole (SMX). TMP’s mechanism is based on the
reduction of tetrahydrofolate (FAH4) production which
is normally needed for cell growth and survival by
inhibiting reductase activity. Its antimicrobial activity is
enhanced when combined with SMX since it blocks the
synthesis of FAH2 at the same time (V
azquez-L
opez et al.
2020).
Other new agents that are currently being investigated
for antimicrobial resistant A. baumannii infections
include cefiderocol and Fosfomycin (Doi 2019).
Journal of Applied Microbiology ©2021 The Society for Applied Microbiology 17
M. Nguyen and S.G. Joshi Carbapenem resistance and Acinetobacter
Cefiderocol is a siderophore cephalosporin that has a cat-
echol side chain forming a chelated complex with ferric
iron (Doi 2019). It is stable against b-lactamases hydroly-
sis and has shown in vitro efficacy against Gram-negative
bacteria such as A. baumannii. For example, a patient
with osteomyelitis caused by extreme drug resistant
(XDR) A. baumannii was successfully treated with surgi-
cal debridement and cefiderocol (Dagher et al. 2020).
Although there were additional reports demonstrating the
safe and efficient use of cefiderocol to treat serious infec-
tions caused by this bacteria, more pharmacokinetic stud-
ies need to be investigated in order to understand the
link between cefiderocol and its bactericidal activity
(Hsueh et al. 2019).
Fosfomycin is a phosphoenolpyruvate analogue that
inhibits early actions of peptidoglycan synthesis (Doi
2019). The agent is effective in treating A. baumannii
infections that are resistant to carbapenems if used in
combination with sulbactam, as seen in a study where fos-
fomycin–sulbactam antibiotic combination was effective
against 74% of the 50 A. baumannii isolates. Further stud-
ies are also needed to understand synergistic fosfomycin–
sulbactam combination (Mohd Sazlly Lim et al.2020).
There is no specific antimicrobial therapeutic strategy
against A. baumannii infections; however, the current,
usual therapeutic regimen involves active b-lactam
monotherapy, combining a b-lactam with an aminogly-
coside and other antimicrobial combination therapies
involving colistin/imipenem, colistin/meropenem, col-
istin/rifampicin, colistin/minocycline, colistin/tigecycline,
colistin/sulbactam, colistin/teicoplanin, colistin/dapto-
mycin, colistin/fusidic acid and imipenem/sulbactam
(V
azquez-L
opez et al. 2020). Overall, the use of combina-
tion therapy seems to be advantageous as it demonstrates
an overall decline in mortality and greater than 14 days
of survival rate and elimination (Weinberg et al. 2020).
Alternative modalities: therapeutic options beyond
antibiotics
Although carbapenem is most commonly used for serious
and suspected infections related to A. baumannii,thereisa
growing prevalence of MDR Acinetobacter species that have
acquired an extensive resistance to these common first-line
antibiotics. Thus, in addition to searching other therapeutic
options that can be used as monotherapy or as part of com-
bination therapy, researchers have developed various alterna-
tive, innovative control strategies for dealing with this
pathogen, which include but not limited to the following:
Bacteriophages
With an increase in antibiotic resistant bacteria, bacterio-
phage therapy (or phage therapy) is a potential
alternative option for the control of MDR A. baumannii
infection (Vrancianu et al. 2020). A. baumannii phages
are usually isolated from wastewater and clinical waste
(Bagi
nska et al. 2019). In order to treat bacterial infec-
tions, phage therapy works by using viral parasites, which
infect the bacteria by detecting surface receptors, injecting
its genes into the host and then replicating itself inside
the host (Vrancianu et al. 2020). Phage therapy may
enhance antibiotic susceptibility of resistant A. baumannii
strains due to its genetic trade-off: if the bacteria develop
a trait for antibiotic resistance, then bacteria may be
more defenceless against phage infection or vice versa,
with higher phage resistance, the bacteria can develop
higher sensitivity levels to antibiotics (Vrancianu et al.
2020; Weinberg et al. 2020). Lytic bacteriophage
monotherapy or in combination with other antibiotics
may be used to reduce the chances of new development
of resistances (Styles et al. 2020). In addition, other
advantages of using phage therapy include absence of
adverse effect on microbiome, high degree of selectivity,
as well as high levels of specificity for pathogens (Vran-
cianu et al. 2020).
Current in vivo and in vitro studies have shown high
efficiency and increased survival rates in the treatment of
mouse models for A. baumannii pneumonia and wound
infection using phage therapy; based on these animal stud-
ies, several other studies have been performed to under-
stand the efficacy of phage therapy against nosocomial
infections (Vrancianu et al. 2020). In 2017, the first human
trial of bacteriophages used against A. baumannii took
place on a 68-year-old diabetic patient with necrotizing
pancreatitis and pancreatic pseudocyst complicated by
MDR A. baumannii infection (Bagi
nska et al.2019).The
results from this clinical application of bacteriophages
show hope for phage therapy for the treatment of critically
ill patients in whom A. baumannii strains were detected;
however, as of now, there is still no regulatory approval
for bacteriophage medicine in the EU or the United States
(Bagi
nska et al. 2019; Styles et al.2020).Somebacterio-
phages, such as vPhT2, can even be made into safe hand
sanitizer or antimicrobial for usage in hospitals (Styles
et al. 2020). This shows additional promise for the use of
phage therapy in the future; however, more studies need
to be conducted in order to fully comprehend phage ther-
apy as a means to fight MDR A. baumannii strains.
Antimicrobial peptides
Another strategy that may help with controlling nosoco-
mial infections involves antimicrobial peptides (AMPs).
They are an intrinsic host immune response by a variety
of prokaryotic and eukaryotic organisms when dealing
with agents such as viruses, bacteria and fungi (Asif et al.
2018; Vrancianu et al. 2020). These peptides’ antimicrobial
Journal of Applied Microbiology ©2021 The Society for Applied Microbiology18
Carbapenem resistance and Acinetobacter M. Nguyen and S.G. Joshi
actions work by damaging cell membrane and cell walls,
inhibiting synthesis of protein and induce apoptosis/necro-
sis (Vrancianu et al. 2020). AMPs have low immunogenic-
ity, low resistance and broad-spectrum actions against
both Gram-positive and Gram-negative bacteria (Butler
et al. 2019). Current research involving AMPs demon-
strates effectiveness against A. baumannii strains. Examples
of AMPs with activity against A. baumannii include a
combination of cecropin A and melittin which has demon-
strated activity in peritoneal sepsis in an animal model
with A. baumannii infection; brevinin 2, alyteserin 2 and
catonic a-helical peptides with bactericidal activity;
proline-rich peptide A3-APO which was more effective
than imipenem at controlling the bacteria in a mice
model; and AMP LL-37 (human AMP) or WAM-1 (mar-
supial AMP) for prevention of biofilm formation (Asif
et al.2018;Weinberget al. 2020). To be considered for
therapy, AMPs need to be further developed in order to
improve efficacy by increasing its specificity against infec-
tious agents, reducing cytotoxicity to mammalian cells,
increasing stability and lowering costs by making peptides
as short as possible (Vrancianu et al.2020).
CRISPR technology
Another strategy that can be used against MDR A. bau-
mannii infections is CRISPR (clustered regularly inter-
spaced short palindromic repeat) system. The CRISPR
system is related to cas9 nuclease and single-guide RNA
(sgRNA) transcript along with other structural elements.
CRISPR systems target mobile genetic elements when
sgRNA binds to Cas 9 nuclease, which introduces
double-stranded breaks at the ends of target DNA and
subsequently cleavage (Vrancianu et al. 2020). This sys-
tem can therefore be used to knock out the resistance
determinants for use in antimicrobial therapy by editing
the genome of antibiotic-resistant bacterial strains (Asif
et al. 2018). CRISPR is advantageous for its high speci-
ficity caused by the presence of short, repetitive sequences
in CRISPR loci that are separated from each other by sin-
gle sequences of 26–72 pairs of lengths obtained from
plasmids, transposons or other mobile genetic elements.
CRISPR is a novel therapeutic way to control MDR A.
baumannii outbreaks; however, it has limitations in
managing infections including off-target mutations, speci-
fic protospacer adjacent motif (PAM) sequences require-
ment and the delivery of protein–RNA complex through
bacterial membrane (Vrancianu et al. 2020). More studies
should therefore be conducted to confirm its use in con-
trolling bacterial resistance.
Metal chelators
In order to handle A. baumannii infections, metal chela-
tors such as iron or zinc can be used for designing newer
drugs since they are important in the expression of bacte-
rial virulence factors. Artificial nanoparticles called lipo-
somes can mimic host cell membranes and act as baits
for bacterial toxins to subsequently neutralize them (Asif
et al. 2018).
Vaccines
The discovery of vaccines against A. baumannii is a cost-
effective, promising strategy in order to help vulnerable
populations such as immunocompromised patients and
the elderly (Fereshteh et al. 2020). The most recent vacci-
nes candidates based on active and passive immunization
of experimental animals for protection against A. bauman-
nii can be divided into two groups: (i) vaccines with many
components such as formalin-inactivated whole cells, outer
membrane vesicles (OMVs) and other membrane com-
plexes (OMCs); (ii) purified recombinant proteins contain-
ing vaccines such as biofilm-associated protein (Bap),
trimeric autotransporter protein (Ata), Omp A, poly-N-
acetyl-b-(1,6)-glucosamine (PNAG), small protein A and
phospholipase D, Omp22, putative pilus assembly protein
(FilF), NucAb, BamA, and K1 capsular polysaccharide
(Peri et al. 2019; Yang et al. 2020). Although the first
group of vaccines showed promising results in the mouse
model, its efficacy for human use is limited by substantial
lipopolysaccharides quantity and human injection stan-
dardization. As for the other group of vaccines, the lack of
consistency and the frequency of these proteins among
clinical strains make it difficult to achieve a broadly pro-
tective vaccine (Fereshteh et al.2020).
In addition, recent studies have combined comparative
genome analysis and in vitro proteomics with reverse vac-
cinology methods in order to determine potential vaccine
targets (Mujawar et al. 2019). The utilization of vaccines
to decrease the infection rate of MDR A. baumannii is a
promising alternative strategy; however, a licensed vaccine
does not currently exist. More research needs to be done
for the development of vaccines and the hunt for an ideal
vaccine and/or drug candidate against A. baumannii
infection is still in progress (Mujawar et al. 2019;
Fereshteh et al. 2020; Li et al. 2020).
Concluding remarks
Overall, carbapenems, often in combination with other
agents, are the cornerstone of therapy for serious
hospital-acquired infection; however, Acinetobacter species
play a major role in hospital-acquired infections and is
characterized by increasing antimicrobial resistance. In
this review, we discussed major characteristics that make
A. baumannii such a prominent nosocomial pathogen,
such as its virulence factors, desiccation resistance and
mechanisms of carbapenem resistance. As of now, strict
Journal of Applied Microbiology ©2021 The Society for Applied Microbiology 19
M. Nguyen and S.G. Joshi Carbapenem resistance and Acinetobacter
implementation of infection control measures such as
environmental decontamination, proper hand sanitation
compliance, antibiotic stewardship programme, methods
for rapid detection of carbapenemase genes and combina-
tion therapy may help with slowing down the develop-
ment of resistance and decreasing high resistance rates.
However, with the growing emergence of MDR A. bau-
mannii, there is a further need for the development of
novel antibiotics, rapid and accurate tools for organism
identification and alternative anti-virulence treatment
strategies. A combined effort by the government, indus-
try, scientific community, clinicians and other healthcare
workers is necessary to effectively treat severe nosocomial
infections and to decrease the frequency and chances of
outbreaks caused by A. baumannii.
Authors’ contributions
The article topic conceptualized SGJ, both, MN and SGJ
made literature searches, MN did a detailed research on
current-status, and prepared original draft, both authors
discussed details, reviewed and edited it. All authors have
read and agreed to the publication version of the manu-
script. All authors warrant that the paper has neither
been published previously nor is being considered for
publication elsewhere.
Conflicts of Interest
The authors declare no conflict of interest.
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