ADR-12644; No of Pages 11

Advanced Drug Delivery Reviews xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Advanced Drug Delivery Reviews

journal homepage: www.elsevier.com/locate/addr

Mechanisms of β-lactam antimicrobial resistance and epidemiology of

major community- and healthcare-associated
multidrug-resistant bacteria☆
Sarah S. Tang a,1, Anucha Apisarnthanarak b,1, Li Yang Hsu c,⁎
a
Singapore General Hospital, Outram Road, Singapore 169608, Singapore
b
Thammasat University Hospital, Pathumthani 12120, Thailand
c
National University Health System, 1E Kent Ridge Road, NUHS Tower Block Level 10, Singapore 119228, Singapore

a r t i c l e i n f o a b s t r a c t

Article history: Alexander Fleming's discovery of penicillin heralded an age of antibiotic development and healthcare advances
Accepted 11 August 2014 that are premised on the ability to prevent and treat bacterial infections both safely and effectively. The resultant
Available online xxxx evolution of antimicrobial resistant mechanisms and spread of bacteria bearing these genetic determinants of
resistance are acknowledged to be one of the major public health challenges globally, and threatens to unravel
Keywords:
the gains of the past decades. We describe the major mechanisms of resistance to β-lactam antibiotics – the
Antimicrobial resistance
Methicillin-resistant Staphylococcus aureus
most widely used and effective antibiotics currently – in both Gram-positive and Gram-negative bacteria, and
Vancomycin-resistant enterococci also briefly detail the existing and emergent pharmacological strategies to overcome such resistance. The global
Carbapenem resistance epidemiology of the four major types of bacteria that are responsible for the bulk of antimicrobial-resistant infec-
Enterobacteriaceae tions in the healthcare setting – methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci,
β-Lactamases Enterobactericeae, and Acinetobacter baumannii – are also briefly described.
Acinetobacter baumannii © 2014 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2. General mechanisms of antimicrobial resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3. Antimicrobial susceptibility testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4. β-Lactam resistance in Gram-positive bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4.1. S. aureus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4.2. Enterococci . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4.3. Drug development against Gram-positive bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
5. β-lactam resistance in Gram-negative bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
5.1. Enterobacteriaceae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
5.2. A. baumannii . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
5.3. Drug development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
6. Drug delivery mechanisms to overcome antibiotic resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
7. Global epidemiology of major antimicrobial-resistant bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
7.1. MRSA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
7.2. Vancomycin-resistant enterococci (VRE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
7.3. ESBL-producing Enterobacteriaceae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
7.4. Carbapenem-resistant Enterobacteriaceae (CRE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
7.5. Carbapenem-resistant A. baumannii (CRA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Emergence of multidrug resistance bacteria: Important role of macromolecules as a new drug targeting mi-
crobial membranes”.
⁎ Corresponding author at: Department of Medicine, National University Health System, 1E Kent Ridge Road, NUHS Tower Block Level 10, Singapore 119228, Singapore. Tel.: +65 6772
3931; fax: +65 6779 5678.
E-mail addresses: sarah.tang.s.l@sgh.com.sg (S.S. Tang), anapisarn@yahoo.com (A. Apisarnthanarak), liyang_hsu@yahoo.com (L.Y. Hsu).
1
These authors contributed equally to the work.

http://dx.doi.org/10.1016/j.addr.2014.08.003
0169-409X/© 2014 Elsevier B.V. All rights reserved.

Please cite this article as: S.S. Tang, et al., Mechanisms of β-lactam antimicrobial resistance and epidemiology of major community- and
healthcare-associated multidrug-resistant..., Adv. Drug Deliv. Rev. (2014), http://dx.doi.org/10.1016/j.addr.2014.08.003
2 S.S. Tang et al. / Advanced Drug Delivery Reviews xxx (2014) xxx–xxx

8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

1. Introduction
Antibiotics have been hailed as one of the greatest medical advances
in the modern age [1]. Alexander Fleming's serendipitous observation of
a zone of inhibition around Penicillium notatum on a staphylococcal cul-
ture plate in 1928 is considered one of the most significant milestones in
the timeline of antibiotic discovery, although it took more than a decade
before penicillin was successfully isolated and purified, and underwent
large-scale production and use [2]. However, Fleming's less celebrated
observation was that non-lethal concentrations of penicillin could rap-
idly generate penicillin-resistant microbes [2], a process of evolution
that has held true for all antimicrobial agents used in humans to date.
As illustrated in Fig. 1, the accelerated growth, diversity and burden
of antimicrobial resistance became increasingly evident past the mid-
1970s, although this was initially matched by the development of anti-
microbial compounds that could overcome or bypass these resistance
mechanisms. Since the 1990s, however, there has been a “discovery
void” in the development of new classes of antimicrobial compounds,
a problem compounded by the relentless increase in new and modified
mechanisms of antimicrobial resistance in disease-causing microbes
[3–5]. In the β-lactam class of antibiotics – the largest antibiotic
class containing arguably the most important and effective antibiotics
developed to date – there has been a ten-fold increase in the types of
inactivating enzymes between 1990 and 2010 [6]. The reasons for the
“discovery void” and current imbalance between antimicrobial resis-
tance and development have been described in detail in several other
excellent reviews and will not be further elaborated here [3–5].
Multiple attempts have been made to quantify the local and global
impact of antimicrobial resistance, and these were extensively covered
in recent reviews and reports [4,5]. To summarize, antimicrobial resis-
tant infections result in greater mortality, morbidity and costs of treat-
ment compared to infections caused by their antimicrobial susceptible
counterparts, and the growing inability to prevent infections with anti-
microbial prophylaxis will overwhelmingly and negatively affect the
risk equation in performing more complex medical procedures such as
major surgery, cancer chemotherapy or organ/stem cell transplantation
[4,5]. This burden is unevenly distributed at present, affecting patients
and healthcare systems in lower income and less developed countries
more than those in the developed nations as a consequence of issues of
hygiene and healthcare access [4]. Nonetheless, a post-antibiotic era –
if this should ever arise – will profoundly affect all.
In this review, we focus on the mechanisms of resistance – in partic-
ular β-lactam resistance – as well as the existing and emergent pharma-
cological strategies to overcome such resistance. We also briefly
describe the global epidemiology of the four major types of bacteria
that are responsible for the bulk of antimicrobial-resistant infections
in the healthcare setting — methicillin-resistant Staphylococcus aureus,
vancomycin-resistant enterococci, Enterobactericeae, and Acinetobacter
baumannii.
2. General mechanisms of antimicrobial resistance
Bacteria can acquire antibiotic resistance either through de novo gene
mutation(s) or by horizontal transfer of mobile genetic elements.
Mutation-based changes are usually spontaneous and random, involving
single nucleotide polymorphisms that occur at a rate of 10−9 to 10−10 per
gene. Consequently, drug targets may be altered, enzymes capable of
inactivating the antibiotic may be expressed, efflux systems may be
up-regulated and uptake mechanisms may be lost [7]. In some instances,
mutations occur in the regulatory genes or may not result in changes in
protein function at all. This route of resistance development is often
deemed to be of lesser importance as cumulative point mutations are usu-
ally required for phenotypic resistance, although it is possible for the
strain harboring the mutated allele to become the predominant organism
under selective pressure such as antimicrobial drug use. In contrast, cen-
tral to the rapid and broad propagation of drug resistance is the ability for
bacteria to undergo horizontal gene transfer. Antibiotic resistance genes
are carried on mobile genetic elements such as transposons, integrons
and plasmids (extrachromosomal genetic material that may be large
and can contain a variety of resistance genes), which serve as vectors
for transfer within the same species or between different species via
processes of conjugation, transformation and transduction. Genetic
mechanisms of antibiotic resistance and their consequences have been
previously reviewed [8–11].

Fig. 1. Timeline of antimicrobial drug discovery against the development of antimicrobial drug resistance.

Please cite this article as: S.S. Tang, et al., Mechanisms of β-lactam antimicrobial resistance and epidemiology of major community- and
healthcare-associated multidrug-resistant..., Adv. Drug Deliv. Rev. (2014), http://dx.doi.org/10.1016/j.addr.2014.08.003
 S.S. Tang et al. / Advanced Drug Delivery Reviews xxx (2014) xxx–xxx
Basic mechanisms of antibiotic resistance can generally be summa-
rized using the bullet–target concept [12]. Sites of drug activity (target)
may be altered by enzymatic modification (e.g. methylation of 16S rRNA
in aminoglycoside resistance), transformed by genomic mutations (e.g.
DNA gyrase in quinolone resistance), and/or bypassed metabolically
(e.g. sulfonamide resistance). On the other hand, the antibiotic (bullet)
can undergo enzymatic inactivation (e.g. acetylation of aminoglyco-
sides) and degradation (e.g. β-lactams by β-lactamases), reduced acces-
sibility in entering the bacteria cell (e.g. porin loss) and/or increased
extrusion from the cell (e.g. efflux pump) [13,14]. Fig. 2 depicts the com-
mon mechanisms of β-lactam antibiotic resistance by both Gram-positive
and Gram-negative bacteria.
3. Antimicrobial susceptibility testing
Antimicrobial resistance detection in bacteria is generally performed
in clinical and research microbiology laboratories using phenotypic
susceptibility testing methods. These are variants of detection of micro-
bial growth from an initial specified amount and/or concentration of
bacteria inoculated into culture media with stepwise dilution of target
antimicrobial concentrations. The most commonly used methods –
disk susceptibility testing, broth dilution, Etest strips, and automated sys-
tems – have been reviewed elsewhere [15]. Such methods produce ei-
ther qualitative (disk susceptibility testing) or quantitative results, and
both the testing as well as the interpretation of test results – especially
in the clinical setting – are usually based on regularly updated standards
published by expert bodies such as the European Committee on Antimi-
crobial Susceptibility Testing (EUCAST) [16] or the Clinical Laboratory
Standards Institute (CLSI) [17].
Phenotypic susceptibility testing methods are generally not able to
define the exact mechanism of resistance, although an accurate guess
can usually be made based on a combination of the distribution of test
results as well as the species of microorganism tested [15]. The increas-
ing availability and reduced costs of next generation sequencing renders
whole genome sequencing an attractive possibility for bacterial resistance
detection — and the results have been excellent in certain organisms such
as S. aureus [18]. Nonetheless, for bacteria where novel resistance mecha-
nisms emerge frequently, whole genome sequencing and other molecular
methods may not be able to detect significant antibiotic resistance as re-
liably as phenotypic methods [15].
Fig. 2. Major mechanisms of β-lactam resistance in both Gram-positive and Gram-negative bacteria.
Please cite this article as: S.S. Tang, et al., Mechanisms of β-lactam antimicrobial resistance and epidemiology of major community- and
healthcare-associated multidrug-resistant..., Adv. Drug Deliv. Rev. (2014), http://dx.doi.org/10.1016/j.addr.2014.08.003
3
4. β-Lactam resistance in Gram-positive bacteria
β-Lactam antibiotics exert bactericidal activity by covalently binding
to and inactivating enzymes known as penicillin-binding proteins
(PBPs), resulting in interference with the synthesis and remodeling of
the bacterial peptidoglycan. In Gram-positive bacteria, β-lactam resis-
tance primarily occurs as a result of alteration of PBPs, with enzymatic
degradation as a minor pathway (Fig. 2).
4.1. S. aureus
Penicillin was the primary antibiotic used for S. aureus infections
until the late 1950s when penicillinase-producing S. aureus became a
major problem, particularly during the Asian influenza pandemic
when such bacteria frequently caused post-influenza pneumonia [19].
The β-lactamase produced is encoded by the blaZ gene, which in turn
is regulated by two adjacent genes, the repressor blaI and anti-
repressor blaR1 [20]. In the presence of β-lactam antibiotics, blaR1 pro-
tein undergoes autolytic cleavage to become a protease for the cleavage
of the blaI protein, thereby unblocking the transcription of the blaZ gene
[21].
Methicillin, first-generation cephalosporins and subsequently the
other semi-synthetic penicillinase-resistant penicillins (cloxacillin,
flucloxacillin) were introduced in the late 1950s–early 1960s. Unfortu-
nately, this strategy was short-lived as methicillin-resistant S. aureus
(MRSA) appeared at the start of the 1960s [22]. Methicillin resistance
is not mediated by β-lactamase production but by the expression of a
unique PBP (PBP 2a), which is in addition to the four PBPs (PBP1–4)
present in native S. aureus. PBP2a has low affinity for all β-lactam anti-
biotics and acts as a substitute for the other PBPs, thus enabling the sur-
vival of the bacteria in the presence of high concentrations of β-lactam
antibiotics [23]. The gene encoding PBP2a is known as mecA and is locat-
ed in a specific mobile genetic element referred to as the staphylococcal
cassette chromosome mec (SCCmec) that integrates into the chromo-
some using recombinases (ccrAB or ccrC) carried on the SCCmec
element itself [24]. Similar to the blaZ system, PBP2a synthesis is regu-
lated by mecR1 and the repressor gene mecI; in addition, due to high
sequence homology with the proteins, expression of PBP2a can be in-
duced by the blaR1–blaI–blaZ system, if present. Constitutive expression
of methicillin resistance, on the other hand, requires activation of the
4 S.S. Tang et al. / Advanced Drug Delivery Reviews xxx (2014) xxx–xxx
mecA gene by the mutation or deletion of the mecI gene or a mecA
promotor/operator region [24].
Expression of methicillin resistance, however, also involves several
other factors. PBP2a, lacking a functional glycosyltransferase region,
requires the co-existence of PBP2 to effectively make peptidoglycan
[25]; hence deletion of PBP2 will reduce the ability of PBP2a to confer
resistance. The fem (factor essential for methicillin resistance) or aux
(auxiliary) factors, including llm, fmtA and sigB, have also been identified
to alter the expression of resistance. These genes are located on chromo-
somal DNA separate from the mec element and are also involved in
peptidoglycan synthesis [26,27].
4.2. Enterococci
The intrinsic resistance of enterococci to β-lactam antibiotics stems
from the production of low-affinity PBP5 that is able to function in
place of other PBPs that are already saturated by β-lactam antibiotics.
Minimum inhibitory concentrations (MICs) of ampicillin, penicillin,
piperacillin and imipenem have been reported to be approximately
100-fold higher than that for streptococci [28], with MICs of penicillin
against Enterococcus faecalis and Enterococcus faecium typically in the
ranges of 2–8 μg/ml and 8–16 μg/ml respectively [29]. Deletion of
PBP5 is associated with an 800-fold reduction in MIC of ampicillin
[30]. Accordingly, this low-level resistance renders penicillins bacterio-
static and cephalosporins practically ineffective.
Molecular mechanisms for intrinsic cephalosporin resistance have
yet to be clearly defined. Apart from inherent differences in binding af-
finity to PBP5, a two-compartment signal transduction system (croRS)
and a Ser/Thr kinase, known as ireK (as for intrinsic resistance of entero-
cocci) and which is reciprocally regulated by the upstream protein
phosphatase ireP, have been reported to be important factors of cepha-
losporin resistance [31,32]. IreB, which is found downstream of ireK, has
also recently been described to contribute to cephalosporin resistance
through ireK-dependent phosphorylation [33].
High level resistance to β-lactams develops through acquisition of β-
lactamases or mutations in PBP5. The β-lactamases in enterococci are
encoded by plasmid-mediated bla genes, which are highly homologous
to the blaZ genes of S. aureus, except for its constitutive expression
presumably due to a lack of a repressor protein [28]. Resistance due to
this mechanism is nonetheless rare and has been described predomi-
nantly in E. faecalis rather than E. faecium isolates [29]. Resistance in
E. faecium has been attributed to modulations in PBP5 — mutations in
its penicillin binding site that causes further reduction in binding affin-
ity to β-lactams and/or its overproduction. In particular, the former has
been implicated in the development of highly resistant strains that have
MICs of ampicillin up to 512 μg/ml [34].
4.3. Drug development against Gram-positive bacteria
Drug discovery and development against Gram-positive bacteria is
primarily directed at the cell wall, in particular, the PBPs. As bacteria
evolve in terms of their PBP expression, new compounds that exhibit
greater binding affinity to current PBPs and/or are capable of inhibiting
new PBPs have been designed. For instance, the newly approved ceph-
alosporins (ceftobiprole and ceftaroline) confer anti-MRSA activity by
their ability to bind to and inhibit PBP2a, whereas several noncovalent
compounds appear to be promising PBP2a inhibitors capable of restor-
ing β-lactam antibiotic susceptibility to MRSA [35,36].
Other strategies to modulate methicillin resistance have also been
explored and include (i) inhibition of mRNA expression of mecA (e.g.
polyoxometalates), (ii) use of DNAzymes to disrupt the bla and mec
signal pathways (e.g. PS-DRZ1366 and PS-DRZ1694), (iii) inhibition of
Mur enzymes (e.g. fosfomycin), (iv) interference with cell wall precursor
lipid I and lipid II (e.g. defensin mimetic BAS00127538), (v) blocking bio-
synthesis of wall teichoic acids (e.g. 1835F03 and targocil), (vi) direct
Please cite this article as: S.S. Tang, et al., Mechanisms of β-lactam antimicrobial resistance and epidemiology of major community- and
healthcare-associated multidrug-resistant..., Adv. Drug Deliv. Rev. (2014), http://dx.doi.org/10.1016/j.addr.2014.08.003
disruption of the cell wall (e.g. pore-forming drug, brilacidin), and (vii) in-
hibition of fatty acid synthesis (e.g. FabI inhibitor, CG400549) [37,38].
In our opinion, β-lactams that can directly bind to altered PBPs (such
as ceftobiprole against PBP2a) are more likely to be effective in the clin-
ical setting and have a higher likelihood of impacting clinical practice in
the short and medium term. Other strategies as described above are
interesting but face significant hurdles in reaching clinical practice, in-
cluding tests of toxicity in animals and humans, pharmacokinetics,
costs of clinical trials to demonstrate efficacy, etc.
5. β-lactam resistance in Gram-negative bacteria
β-Lactam resistance in Gram-negative bacteria can arise through
three possible mechanisms: alteration of PBPs, production of β-
lactamases, and limited access to target PBPs (Fig. 2). In contrast to
Gram-positive bacteria, PBPs are located in the periplasmic space of
Gram-negative bacteria and β-lactam antibiotics must traverse across
the bacterial outer membrane in order to reach their target sites of ac-
tion. Hence, any modulation that restricts entry (porin loss) or result
in extrusion (efflux pumps) of β-lactam antibiotics will confer antibiotic
resistance, with the potential for cross-resistance to multiple agents
should these drugs share the same channel. This mechanism of resis-
tance is unique to Gram-negative bacteria. In addition, while changes
in PBPs are the foundational basis for antibiotic resistance in Gram-
positive bacteria, they occur less frequently in Gram-negative bacteria,
in which production of β-lactamases is the most prevalent resistance
mechanism [39]. Of note, the synergy achieved through the interplay
of these diverse mechanisms plays an important role in determining
the final phenotypic expression of resistance in Gram-negative bacteria.
5.1. Enterobacteriaceae
The profound impact of β-lactamases on antimicrobial resistance is
most evident in this group of bacteria. Interestingly, the first bacterial
enzyme reported to destroy penicillin was an AmpC cephalosporinase
identified from Escherichia coli in 1940, several years before the
introduction of penicillin into clinical practice [40]. Several schemes of
classification have been proposed to characterize the vast number of
β-lactamases identified. A commonly used system is the Ambler molec-
ular classification scheme whereby enzymes are grouped based on pro-
tein homology — the need for serine in its active site (class A, C and D
serine-β-lactamases) and those that require zinc (class B metallo-β-
lactamases) [41]. Another commonly used scheme is the Bush–Jacoby–
Medeiros functional classification system that categorizes the β-
lactamases into four main groups according to their substrate and inhib-
itory properties. This system, which was originally proposed in 1995, was
updated and expanded by Bush and Jacoby in 2010 [42]. A list of β-
lactamases in both classification systems is shown in Table 1.
Characteristics of the various β-lactamases have been extensively
reviewed in previous publications [42–47], and will only be briefly
touched upon here. Extended-spectrum β-lactamases (ESBLs) are prod-
ucts of point mutations in class A β-lactamases TEM-1, TEM-2 and SHV-
1 that lead to broadening of their substrate specificity. These enzymes
confer resistance to penicillins, first-, second-, and third-generation
cephalosporins as well as aztreonam, but are inhibited by β-lactamase
inhibitors and are not active against the cephamycins (e.g. cefoxitin)
[48]. Cefepime resistance may be more frequent with the CTX-M-type
ESBL and its susceptibility appears to be dependent on the inoculum
of the pathogen [46]. The CTX-M ESBLs, which are related to the chro-
mosomal β-lactamases of the environmental Kluyvera species, emerged
in the late 1980s and have since become very prevalent [49]. CTX-M en-
zymes typically hydrolyze cefotaxime more readily than ceftazidime,
and unlike the TEM and SHV ESBLs, are more susceptible to inhibition
by tazobactam than clavulanic acid [44,46,49]. OXA-type ESBLs are rare-
ly found in Enterobacteriaceae.
 S.S. Tang et al. / Advanced Drug Delivery Reviews xxx (2014) xxx–xxx 5

Table 1
Classification of bacterial β-lactamases (illustration of both the Ambler [33] and Bush–Jacoby classifications [34]).

Ambler Bush– Characteristics Examples of enzymes Substrates Specific laboratory confirmation

Jacoby method(s)

A 2a Penicillinases inhibited by CA1 PC1 Penicillins

2b Broad-spectrum enzymes inhibited TEM-1, TEM-2, TEM-13, SHV-1, Penicillins, cephalothin
by CA1 SHV-11
2be Extended broad-spectrum enzymes TEM-3, TEM-10, TEM-26, SHV-2, Penicillins, oxyimino-cephalosporins Cephalosporin/CA synergy double-
inhibited by CA1 SHV-3, Klebsiella oxytoca K1, CTX- (cefotaxime, ceftazidime, ceftriaxone, disk test, ESBL Etest
M, PER, VEB cefepime), monobactams
2br Broad-spectrum enzymes with TEM-30, TEM-31, SHV-10, SHV-72 Penicillins, resistant to CA, tazobactam and
reduced binding to CA1 (inhibitor- sulbactam
resistant TEMs)
2ber Extended-spectrum enzymes with TEM-50, TEM-158 Penicillins, oxyimino-cephalosporins,
relative resistance to CA1 monobactams, resistant to CA, tazobactam
and sulbactam
2c Carbenicillin-hydrolyzing enzymes PSE-1, CARB-3 Penicillins, carbenicillin
inhibited by CA1
2ce Extended-spectrum carbenicillinase RTG-4 (CARB-10) Carbenicillin, cefepime
2e Cephalosporinases inhibited by CA1 CepA Cephalosporins
2f Carbapenem-hydrolyzing KPC, SME, GES, IMI-1 All β-lactams, including carbapenems Modified Hodge test, Carba NP test
nonmetallo-β-lactamases
B 3 Metallo-β-lactamases IMP, VIM, IND All β-lactams, including carbapenems, with Modified Hodge test, Carba NP test
exception of monobactams
C 1 Cephalosporinases not inhibited by ACT-1, FOX-1, MIR-1, CMY Narrow and extended-spectrum cephalo- Cefoxitin/cloxacillin synergy
CA1 sporins, including cephamycins double-disk test, AmpC Etest,
modified Hodge test
D 2d Cloxacillin-hydrolyzing enzymes OXA-1, OXA-2, OXA-10 Cloxacillin, oxacillin
2de with variable inhibition by CA1 OXA-11, OXA-15 Cloxacillin, oxacillin, oxyimino-
cephalosporins, monobactams
2df OXA-23, OXA-51, OXA-58 Cloxacillin, oxacillin, carbapenems Modified Hodge test, Carba NP test
– 4 Penicillinases not inhibited by CA1 Penicillinases from Burkholderia Penicillins
cepacia
1
CA — clavulanic acid.

AmpC β-lactamases are characteristically resistant to inhibition by β-
lactamase inhibitors and provide resistance to oxyimino-cephalosporins
along with the cephamycins; fourth-generation cephalosporins (e.g.
cefepime) are considerably more stable [50]. Most Enterobacteriaceae,
apart from Klebsiella spp. and Proteus spp., have chromosomal AmpC
genes that are constitutively expressed at low levels. Expression of
the blaAmpC gene, however, is inducible by derepression on exposure to
β-lactam antibiotics such as amoxicillin, imipenem and clavulanic acid.
In E. coli, high levels of resistance to cephalosporins can also occur either
through up-regulation of the chromosomal AmpC gene or through the ac-
quisition of a plasmid-borne AmpC gene that is unaccompanied by regu-
latory genes [47].
Once thought to be rare, carbapenem-resistant Enterobacteriaceae
(CRE) have been labeled an urgent (highest level) health threat as of
2013 [51], with few effective antimicrobial agents against infections
caused by these organisms other than the polymyxins and tigecycline
(because such organisms typically are also resistant to the majority of
non-β-lactam antibiotics through other mechanisms of resistance).
Two groups of enzymes have been associated with carbapenem resis-
tance — the metallo-β-lactamases and non-metallo-β-lactamases. The
metallo-β-lactamases have a comparatively broader spectrum of activ-
ity as they exhibit strong hydrolytic activity against all β-lactam antibi-
otics except for monobactams (i.e. aztreonam), and are not inhibited by
β-lactamase inhibitors. The group of non-metallo-β-lactamases include
the class A carbapenemases and class D OXA-type carbapenemases.
Class A carbapenemases of the SME and IMI families can confer resistance
to penicillins and aztreonam but not the oxyimino-cephalosporins; the
Klebsiella pneumoniae carbapenemase (KPC) carbapenemases confer re-
sistance to all β-lactam antibiotics and are plasmid-encoded, and are
therefore potentially able to spread between Enterobacteriaceae with
greater facility [50]. The OXA-type carbapenemases confer high level re-
sistance to penicillins, have some hydrolytic activity against carbapenems
(imipenem more so than meropenem), but generally do not affect the
cephalosporins and monobactams [52]. In contrast to the metallo-β-
lactams, the non-metallo-β-lactamases have fairly weak hydrolytic
activity [53]. Nonetheless, high level resistance to carbapenems can
arise from synergy with loss of outer membrane proteins (OMPs). Carba-
penem resistance can also occur in porin-deficient AmpC β-lactamase or
ESBL-producing isolates, although this mechanism is considered of lesser
clinical and public health importance because of the reduced risk of trans-
mission of resistance compared to plasmid-borne β-lactamase genes.
5.2. A. baumannii
A. baumannii has inherent chromosomally-encoded AmpC-type
cephalosporinases, now referred to as ADCs (Acinetobacter derived
cephalosporinases), that has not been shown to be inducible. Rather, it
is constitutively expressed but at low levels inadequate to affect its an-
tibiotic susceptibility profile. Nonetheless, resistance to penicillins and
cephalosporins, with the exception of cefepime, can develop upon up-
stream acquisition of insertion sequence ISAba1, and less frequently
ISAba125, which serve as strong promoters for the overproduction of
the enzyme [54,55]. Extended-spectrum AmpC-type cephalosporinases
(ESAC), such as ADC-33 and ADC-56, have been described as being ca-
pable of hydrolyzing all cephalosporins including cefepime [56,57].
A. baumannii also produces an intrinsic chromosomally-encoded
oxacillinase (OXA-51 and its variants). In like manner to the ADCs,
genes encoding for these oxacillinases are normally expressed at low
levels but can be up-regulated and thereby confer carbapenem resis-
tance when ISAba1 or ISAba9 is inserted upstream [58].
Acquired β-lactamases include penicillinases (TEM-1, TEM-2 and
CARB-5), class D oxacillinases that lack carbapenemase activity but
are clavulanic acid-resistant (OXA-20, OXA-21 and OXA-37), and the
extended-spectrum β-lactamases (ESBLs). Although the penicillinases
are generally regarded to be susceptible to inhibition by common
β-lactamase inhibitors, production of TEM-1 has been associated with
sulbactam resistance [59]. Genes reported to encode for ESBL production
include blaPER-1, blaPER-2, blaPER-7, blaVEB-1, blaCTX-M, blaSHV-5, blaSHV-12,
blaTEM-92 and blaTEM-116 [60]. In addition, RTG-4 (CARB-10), which is a
unique plasmid-encoded CARB-type β-lactamase that hydrolyzes

Please cite this article as: S.S. Tang, et al., Mechanisms of β-lactam antimicrobial resistance and epidemiology of major community- and
healthcare-associated multidrug-resistant..., Adv. Drug Deliv. Rev. (2014), http://dx.doi.org/10.1016/j.addr.2014.08.003
6 S.S. Tang et al. / Advanced Drug Delivery Reviews xxx (2014) xxx–xxx

cefepime more significantly than ceftazidime and cefotaxime, has been

identified [61].
The major problem with widespread development of carbapenem-
resistant A. baumannii and outbreaks arises from its ability to acquire
carbapenem-hydrolyzing β-lactamases, specifically the Ambler class B
metallo-β-lactamases and class D oxacillinases. Metallo-β-lactamases
are notably the most potent of the carbapenemases, although it is less
common than the OXA-type [62]. Four groups of metallo-β-lactamases
have been described thus far — imipenemase (IMP)-type, Verona
integrin-encoded metallo-β-lactamase (VIM)-type, SIM-1 and New
Delhi metallo-β-lactamase (NDM-1 and NDM-2). Apart from aztreo- Fig. 3. Mechanism of action of β-lactamase-inhibitor combinations, where the β-lactam
nam, these enzymes have the ability to hydrolyze all β-lactams. The antibiotic particles (green polygon) are able to bind with their target penicillin-binding
OXA carbapenemases have been classified into four clusters: (i) OXA- proteins (blue blocks) because the β-lactamase inhibitors (red polygons) bind to and in-
23-like (OXA-23, OXA-27 and OXA-49); (ii) OXA-24-like (OXA-24, hibit bacterial β-lactamases (purple blocks). (For interpretation of the references to
color in this figure legend, the reader is referred to the web version of this article.)
OXA-25, OXA-26, OXA-40 and OXA-72); (iii) OXA-58 and (iv) OXA-
143-like (OXA-143 and OXA-231) [63–65]. OXA-23, which can be either
intra-abdominal infections [73,74], and appears to have an important ad-
chromosome or plasmid mediated, was the first OXA-type β-lactamase
vantage over clavulanic acid — it does not induce AmpC β-lactamase pro-
to be identified from A. baumannii and remains the most prevalent
duction [75].
today. More recently, a novel subclass designated OXA-235-like (OXA-
Another class of agents that displays significant potential is boronic
235, OXA-236 and OXA-237) has been identified from isolates recov-
acid β-lactamase inhibitors (e.g. RPX7009), which exhibit very potent
ered from the U.S. states and Mexico [65]. Carbapenemases belonging
AmpC β-lactamase inhibitory activity when the carboxamide group of
to Ambler class A are also increasingly detected in A. baumannii and
glycylboronates are replaced with a sulfonamide. 4,7-Dichloro-1-
they include KPC-2, KPC-3, KPC-4, KPC-10, and GES-14 [60].
benzothien-2-yl sulfonylaminomethyl (DSABA) is a boronic acid-
A. baumannii is intrinsically resistant to several antimicrobial agents,
based compound that also exhibits activity against OXA β-lactamases
and this is believed to be contributed in part by the small number and
[76].
size of OMPs present, thereby making it less permeable, and/or the
Although the above compounds appear promising, they do not in-
low level constitutive expression of active efflux pumps [66]. To date,
hibit the emerging group of metallo-β-lactamases and there is an urgent
three OMPs have been associated with carbapenem resistance — a
need to develop effective inhibitors against these enzymes in view of
29 kDa protein (also known as CarO), a 33–36 kDa protein and
the changing epidemiology of bacterial resistance. Apart from the thiol
OmpW, which has yet to be fully characterized [60]. An additional
derivatives being the prime candidate, including use of the clinically
43 kDa protein, also referred to as OprD homologue, had been previous-
available anti-hypertensive agent captopril, work has also been per-
ly reported to play a role in carbapenem resistance. However, this claim
formed with classes such as pyridine dicarboxylates, maleic acid deriv-
has since been challenged by newer evidence, which revealed its lack of
atives, carbapenem analogs, and the tricyclic natural products, but none
involvement in carbapenem diffusion, and its closer similarity on genet-
are close to emerging from the developmental pipeline [70,77,78].
ic basis and function to the OprQ protein of Pseudomonas aeruginosa
Just as inhibitor-resistant strains have surfaced with current β-
[67]. The AdeABC efflux pump belongs to the resistance-nodulation-
lactamase inhibitors, it is highly probable that resistance will continue
division (RND) family of efflux systems and has been identified to be
to develop against these novel “second generation” β-lactamase inhibi-
the main efflux mechanism responsible for β-lactam resistance in
tors when they enter clinical use. It is thus necessary to consider addi-
A. baumannii. Upregulation of the gene encoding for this efflux pump
tional strategies to overcome the diverse mechanisms of bacterial
can confer resistance to a broad range of antimicrobial agents, namely
resistance that have been described above so that a multi-pronged ap-
aminoglycosides, β-lactams, fluoroquinolones, tetracyclines, tigecyc-
proach may be adopted. Efflux pump inhibitors are an attractive option
line, macrolides, chloramphenicol, trimethoprim and tigecycline [68].
as adjunctive therapy but their development process has been slow.
Among the class of β-lactam antibotics, cefepime, cefpirome and cefo-
Pagès and Bhardwarj provided a detailed analysis on efflux pump inhib-
taxime are most affected, while it has little impact on the remaining
itors, their ideal characteristics and the list of patented compounds thus
members, including carbapenems. Nonetheless, when present in syner-
far [79,80]. A schematic of the effect of efflux pumps as well as the var-
gy with production of oxacillinases, AdeABC can contribute to high level
ious types of inhibitors is shown in Fig. 4. It has been observed that
carbapenem resistance. AdeIJK is another RND efflux system present in
charge and molecular weight are important determinants of suscepti-
A. baumannii that is capable of extruding β-lactams; AdeFG is the third
bility to extrusion by efflux pump and may be useful parameters for
RND efflux system present, but it has no effect on β-lactam antibiotics
modifying existing compounds.
[69].

5.3. Drug development 6. Drug delivery mechanisms to overcome antibiotic resistance

With new bacterial β-lactamases against which currently available
β-lactamase inhibitors (clavulanic acid, tazobactam, sulbactam) are no
longer active, recent efforts have been directed towards the develop-
ment of novel β-lactamase inhibitors and these have been reviewed in
detail elsewhere [70–72]. Fig. 3 shows the effect of β-lactamase inhibi-
tors in binding β-lactamases while the active drug targets the PBPs.
Among the β-lactamase inhibitors in the pipeline, avibactam and MK-
7655, which belong to the class of non-β-lactam-β-lactamase inhibitors
(diazabicyclooctanes), are at the forefront of the developmental
process. They are active against serine class A, class C and some class
D β-lactamases including ESBLs, AmpC, KPCs and OXA-48. Avibactam
has been successful in clinical trials when paired with ceftazidime
and ceftaroline for the treatment of complicated urinary tract and
It is well recognized that the design of new compounds is an expen-
sive and time-consuming process [81]. There is thus value in exploring
improvements in drug delivery mechanisms as an alternative strategy
to cope with drug-resistant bacteria. The use of nanotechnology for
drug formulation has been utilized largely in the field of oncology and
there are many theoretical benefits to also support its use in the treat-
ment of infectious diseases [82].
β-Lactam antibiotics are readily water-soluble, and thus they general-
ly have poor oral bioavailability (most antibiotics have to be given paren-
terally) and depend on porins for entry into the bacteria. Nanoparticles
are amphiphilic molecules that can be capitalized to increase the solubil-
ity of β-lactam antibiotics, which in turn enhances the ease of oral
drug absorption [82]. The most widely used nanocarrier system are the

Please cite this article as: S.S. Tang, et al., Mechanisms of β-lactam antimicrobial resistance and epidemiology of major community- and
healthcare-associated multidrug-resistant..., Adv. Drug Deliv. Rev. (2014), http://dx.doi.org/10.1016/j.addr.2014.08.003
 S.S. Tang et al. / Advanced Drug Delivery Reviews xxx (2014) xxx–xxx 7

Fig. 4. Schematic of bacterial efflux pump showing (i) extrusion of antibiotic in drug-resistant bacteria, (ii) efflux pump inhibitor plug blocking the outer membrane channel of the pump,
(iii) non-antibiotic molecule as either a competitive or non-competitive inhibitor of the efflux pump affinity binding site, and (iv) modification of the antibiotic molecule to avoid extrusion
by the efflux pump.

liposomes; its lipid bilayer rapidly fuses with the bacterial cell wall, there-
by overcoming the problem of reduced drug uptake, and large quantities
of antibiotic are released directly into the periplasmic space [82,83]. This
high antibiotic concentration can potentially overwhelm β-lactamases
and efflux pumps, rendering them “ineffective” (see Fig. 5). Liposomes
can also be enhanced with “stealth” material (e.g. polyethylene glycol)
that prolongs its circulatory lifetime and/or attached with cell-specific li-
gands (e.g. antibodies, peptides) that allow target binding and release of
high antibiotic concentrations at its intended site [83]. As have already
been seen with liposomal amphotericin B, such tissue specificity could
translate as a toxicity-sparing approach by minimizing unnecessary
drug exposure and injury to other organ tissues.
A slight variation to the liposomes is the polymeric nanoparticle,
which has been evaluated and used for controlled drug release [84].
This feature is particularly valuable for β-lactam antibiotics, whereby
the percentage time (of up to 70%) for which the antibiotic concentra-
tion is kept above the minimum inhibitory concentration is the key de-
terminant of bactericidal activity and optimizing on this parameter
could render the antibiotic effective against bacteria that would have
otherwise been deemed resistant according to conventional antibiotic
dosing regimens. Nonetheless, there are far less data even in the labora-
tory setting with regard to the efficacy of polymeric nanoparticles as an-
tibiotic carriers [85].
In summary, novel drug delivery methods represent an evolutionary
(but not quite revolutionary) advance on the treatment of infectious
diseases, and may be used to overcome many of the current bacterial
antimicrobial resistance mechanisms. Development in this field has
remained slow, however, and there are as yet no clinical trials to deter-
mine the efficacy of such methods in the treatment of human infections.
7. Global epidemiology of major antimicrobial-resistant bacteria
In the past 3 decades, there has been an acceleration in the diversity
and number of antimicrobial resistant bacteria, coinciding with increased
use of antimicrobial agents in both humans and livestock, and better
transportation links [3,5]. Although healthcare facilities have traditionally
been associated with the most resistant bacterial pathogens, the rise of
community- and livestock-associated MRSA and ESBL-producing Entero-
bacteriaceae demonstrate that such bacteria are not limited to healthcare
settings, and pose a potentially escalating threat even in the community
setting [5–7,10].
7.1. MRSA
Since its emergence in UK in the 1960s [22], successive epidemic
strains of healthcare-associated MRSA (HA-MRSA) have spread world-
wide and become entrenched in the hospitals of most countries, with
few exceptions such as West Australia, Holland, and the Scandinavian
countries [86]. The first cases of true community-associated MRSA [87,
88] passed virtually unnoticed by the majority of the medical communi-
ty, until the deaths of four children from severe CA-MRSA infection were
reported from North Dakota and Minnesota in 1997 [89].
Currently, a persistently high number of CA-MRSA infections are
being observed, in particular in the US, but also in increasing frequency
in other parts of the world, reaching pandemic proportions [90,91]. The
CA-MRSA epidemic is particularly severe in the US possibly due to the
higher pathogenic potential of the US epidemic CA-MRSA strain
USA300, which is now also spreading to other countries [90]. At present,
an increasing number of reports from the US and abroad indicates that
CA-MRSA strains may be gradually replacing HA-MRSA strains in hospi-
tals. Several authors have suggested that this indicates yet another po-
tential epidemiological shift in staphylococcal infections [92–94].
Reports of livestock-associated MRSA (LA-MRSA) in European and
Asian animals have increased since 2000 [95,96]. Routine use of antimi-
crobials as growth promoters in animal husbandry appears to be a
possible cause of emerging MRSA carriage [95]. Individuals including
veterinarians and farmers who have been exposed to LA-MRSA colo-
nized livestock are at higher risk for LA-MRSA carriage and infection

Fig. 5. Use of nanocarriers to overcome β-lactamase antibiotic resistance by enhancing drug transport across the cell membrane and saturating β-lactamases produced by the bacteria.

Please cite this article as: S.S. Tang, et al., Mechanisms of β-lactam antimicrobial resistance and epidemiology of major community- and
healthcare-associated multidrug-resistant..., Adv. Drug Deliv. Rev. (2014), http://dx.doi.org/10.1016/j.addr.2014.08.003
8 S.S. Tang et al. / Advanced Drug Delivery Reviews xxx (2014) xxx–xxx
[95,97,98]. Additionally, LA-MRSA was found in 2.5–11.9% of livestock-
derived food products such as pork, turkey, lamb, beef and chicken in
Europe and North America, although infections caused by LA-MRSA
from food products has not been reported to date [99–101].
7.2. Vancomycin-resistant enterococci (VRE)
High-level resistance to the glycopeptide class of antibiotics,
vancomycin and teicoplanin, was first reported in Europe in 1986
[102] and in the US in 1987 [103]. Since then, VRE have been isolated
in multiple countries on several continents and its prevalence is on
the rise [104]. Between 1989 and 1993, the rate of vancomycin resis-
tance reported in the USA by the National Nosocomial Infections Sur-
veillance (NNIS) system increased from 0.3% to 7.9% [105]. The NNIS
system in 2004 showed that 28.5% of enterococcal isolates were resis-
tant to vancomycin — an increase of 12% compared with data averaged
for the years between 1998 and 2002 [106]. In the USA, VRE is found
mainly in patients exposed to healthcare settings. Studies conducted
in the USA in the 1990s failed to detect VRE among farm animals [107,
108]. The situation is different in Europe where a glycopeptide called
avoparcin was used as a growth promoter in the animal industry until
1997 [109]. That led to a high rate of VRE colonization in animals and,
subsequently, in healthy humans via the food chain, either by direct
contact or by eating contaminated products [110]. Fortunately, the
prevalence of VRE in farm animals decreased significantly after
avoparcin was withdrawn [111,112]. In South East Asia, the situation
may be similar since avoparcin has been used in the animal industry
in several Asian countries [113].
7.3. ESBL-producing Enterobacteriaceae
The first definitively characterized ESBL, TEM-3 (cefotaxime-
hydrolyzing enzyme type 1), was discovered in K. pneumoniae iso-
lates recovered from intensive care unit patients in France [114].
Since that initial report, TEM-type enzymes have become the most
diverse class of ESBLs, with N 100 genetic variants now reported
[115]. The prevalence of ESBL-producing Enterobacteriaceae can
vary greatly from one location to another and even over time,
given that ESBL-producing Enterobacteriaceae often arise in focal
outbreaks [116]. As a result, regional and local estimates are proba-
bly more useful to clinical decision-making as compared to global
assessments [116]. A further caveat when reviewing prevalence
data is that different criteria are used to determine whether an En-
terobacteriaceae produces ESBL. Moreover, Enterobacteriaceae that
test positive for ESBL at screening might possess a resistance mech-
anism other than ESBL production (e.g., AmpC-type β-lactamase or
permeability effects that result from changes in OMPs) [116].
The SENTRY Antimicrobial Surveillance Program estimated that the
prevalence of ESBL-producing strains of E. coli and K. pneumoniae in
the United States is relatively low (prevalence of 6–7%) [117–120]. In
contrast, the prevalence of ESBL-producing K. pneumoniae is high in
the Asia-Pacific region (prevalence of 10–25%) and in Latin America.
Data from Latin America suggest that the presence of ESBL-producing
strains of K. pneumoniae has increased dramatically in recent years
(prevalence of 5–46%) [117–120]. In recent years, the spread of
extended-spectrum β-lactamases (ESBLs), particularly CTX-M enzymes,
in Enterobacteriaceae has become a serious public health problem
worldwide [46,121,122]. In fact, ESBL-producing Escherichia coli (ESBL-
EC) are now a frequent cause of infection in the community and in
healthcare centers [122].
7.4. Carbapenem-resistant Enterobacteriaceae (CRE)
Isolated case reports and case series of CRE have increased world-
wide over the last decade [123]. The reported incidence of CRE varies
based on region, study methodology, and setting [124–128]. Notably,
Please cite this article as: S.S. Tang, et al., Mechanisms of β-lactam antimicrobial resistance and epidemiology of major community- and
healthcare-associated multidrug-resistant..., Adv. Drug Deliv. Rev. (2014), http://dx.doi.org/10.1016/j.addr.2014.08.003
the three countries with the highest reported incidences of CRE were
Greece (20–50%), India (4–24%), and the United States (US) (4–11%)
[125,127,129,130]. There is also a keen global interest in infections
due to KPC and NDM-1-producing Enterobacteriaceae. KPC-producing
Enterobacteriaceae were first reported in the US in 1996, with sub-
sequent clonal dissemination through the US and to North Africa,
Europe, China, Canada, Brazil, Argentina, Columbia, and Venezuela
[124,131]. Nonetheless, underreporting of KPC-producing Entero-
bacteriaceae likely exists, given the lack of a structured global sur-
veillance program and difficulties in laboratory detection.
In contrast to the clonal spread of KPC-producing Enterobacteriace-
ae, cases with NDM-1 producing bacteria have been detected world-
wide since the first case was discovered in Sweden in 2008 [132]. The
first recognized endemic region for NDM-1 producing bacteria was
the subcontinent of India, inclusive of Pakistan [124]. Cases of coloniza-
tion or infection with NDM-producing Enterobacteriaceae and non-
Enterobacteriaceae have now been reported from the UK, the US,
Canada, Kenya, China, Australia, Western Europe, and the Middle East
[124,125,133]. Clinical isolates with NDM-1 producing pathogens have
been reported from the respiratory tract, urinary tract, skin and skin
structures, surgical sites, and the bloodstream [124,125,134]. Risk
factors for the acquisition of NDM-1 producing pathogens include
healthcare-associated risks, device-associated risks, severity of illness,
and use of several antibiotics, especially carbapenems, third- and
fourth-generation cephalosporins, and fluoroquinolones [123]. In addi-
tion, the acquisition of NDM-1 producing Enterobacteriaceae can be
food-borne, and repatriation, patient transfers from endemic areas,
and medical tourism have been reported in case reports, case series,
and surveillance studies of these pathogens [123,135,136].
7.5. Carbapenem-resistant A. baumannii (CRA)
Over the last 15 years, CRA has emerged globally as one of the most
challenging pathogens to treat when identified as a healthcare-
associated infection. Before the year 2005, regional variation in CRA
existed, with a range in incidence of 5.6% to 34.5% [137–142]. As report-
ed from reviews dating back to the 1970s [142], healthcare-associated
pneumonia is still the most common infection caused by this organism.
However, in more recent times, infections involving the central nervous
system, skin and soft tissue, and bone have emerged as highly problem-
atic for certain institutions. More recently, countries such as Australia,
Brazil, Singapore, Canada, South Korea, Taiwan, and Thailand have re-
ported CRA incidence rates of 47–80%, with consequent therapeutic
and infection control challenges [123,137,142–144].
Patients with CRA present with a panoply of healthcare-associated
infections such as pneumonia, urinary tract infection, skin and skin
structure infections, and bloodstream infection [123,145]. Patients
with prolonged hospital stay, severe illness, and catheter- or intravascu-
lar device placement have increased risk for CRA acquisition [123,146,
147]. Additionally, colonization with CRA, exposure to other patients
in the same geographic unit with CRA, and exposure to group 2
carbapenems (imipenem-cilastatin, meropenem, and doripenem), and
aminopenicillins are identified risks for CRA infection [145,148,149]. In-
terestingly, the emergence and international spread of CRA is limited to
a small number of epidemic clones, particularly global clones I and II
[150,151].
8. Conclusion
Bacterial antimicrobial resistance has emerged as one of the leading
public health problems globally, with all facts currently suggesting that
the problem will become worse in the future due to the slow develop-
ment of new antimicrobial compounds vis-à-vis the escalating develop-
ment and diversity of antimicrobial resistance mechanisms [3–5]. In
particular, the emergence and spread of β-lactam-resistant bacteria
with an astonishing depth and heterogeneity of resistance mechanisms
 S.S. Tang et al. / Advanced Drug Delivery Reviews xxx (2014) xxx–xxx
within the healthcare and community settings signal the gravity of the
situation, as the β-lactam antibiotics are by far the most widely pre-
scribed and effective of all antimicrobial compounds. There is an urgent
need for a global concerted response towards both development of
novel antimicrobial compounds and strategies, as well as retarding the
spread and further development of antimicrobial-resistant bacteria.
Relevant measures include facilitating as well as speeding up the devel-
opment, testing and approval of new antibiotics and novel drug devel-
opment systems, and segregating different classes of antimicrobial
compounds for human and animal use as far as is possible. Naturally,
better efforts at infection control, surveillance and diagnostics are also
important.
Acknowledgments
We would like to thank A/Prof. Tse Hsien Koh for vetting the
manuscript.
No funding was required for this work.
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