Antimicrobial Resistance in ESKAPE Pathogens

REVIEW
crossm
Antimicrobial Resistance in ESKAPE Pathogens

David M. P. De Oliveira,a,b Brian M. Forde,a,b Timothy J. Kidd,a,b Patrick N. A. Harris,b,c Mark A. Schembri,a,b
Scott A. Beatson,a,b David L. Paterson,b,c Mark J. Walkera,b
a School of Chemistry and Molecular Biosciences, The University of Queensland, QLD, Australia
b Australian Infectious Diseases Research Centre, The University of Queensland, QLD, Australia
c
UQ Centre for Clinical Research, The University of Queensland, QLD, Australia
SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
VANCOMYCIN-RESISTANT ENTEROCOCCI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
KLEBSIELLA PNEUMONIAE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
ACINETOBACTER BAUMANNII . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
PSEUDOMONAS AERUGINOSA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
ENTEROBACTER SPECIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
ESCHERICHIA COLI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
ESKAPE PATHOGEN MECHANISMS OF ANTIBIOTIC RESISTANCE . . . . . . . . . . . . . . . . . . . . . . . . . 8
Antibiotic Inactivation/Alteration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
␤-Lactamases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Aminoglycoside-modifying enzymes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Target Site Modifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Target enzyme modifications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Ribosomal target site alterations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Cell wall precursor alterations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Reduced Antibiotic Penetration and Accumulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Porins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Efflux pumps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Other Mechanisms and Survival Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Biofilms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Antibiotic tolerance and persistence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Intracellular survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
MOBILE GENETIC ELEMENTS CONFERRING ANTIMICROBIAL RESISTANCE . . . . . . . . . . . . . 16
Insertion Sequences and Transposons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Plasmids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Genomic Islands and Integrative Conjugative Elements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Contribution of Horizontal Gene Transfer to the Spread of Mobile Genetic
Elements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Coselection of Antimicrobial Resistance with Detergents and Biocides . . . . . . . . . . . . . . . . . 20
THERAPEUTIC ADVANCES AGAINST ESKAPE PATHOGENS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Recently Approved Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
New Drug Classes in Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
New Drugs in Clinical Trials—Overcoming Antibiotic Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Alternative Drug Trial Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Combinational Drug Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Blocking resistance mechanisms against existing antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
(i) Class I adjuvants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
(ii) Class II adjuvants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Alternative Nondrug Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Citation De Oliveira DMP, Forde BM, Kidd TJ,
Bacteriophage therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Harris PNA, Schembri MA, Beatson SA, Paterson
Repurposing existing drugs used for noninfectious disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
DL, Walker MJ. 2020. Antimicrobial resistance in
Monoclonal antibody therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
ESKAPE pathogens. Clin Microbiol Rev
Vaccine development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
33:e00181-19. https://doi.org/10.1128/CMR
FMT strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
.00181-19.
OUTLOOK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 Copyright © 2020 American Society for
AUTHOR BIOS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 Microbiology. All Rights Reserved.
Address correspondence to Mark J. Walker,
[email protected].
Published 13 May 2020
July 2020 Volume 33 Issue 3 e00181-19 Clinical Microbiology Reviews cmr.asm.org 1

De Oliveira et al. Clinical Microbiology Reviews
SUMMARY Antimicrobial-resistant ESKAPE (Enterococcus faecium, Staphylococcus au-

reus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and
Enterobacter species) pathogens represent a global threat to human health. The ac-
quisition of antimicrobial resistance genes by ESKAPE pathogens has reduced the treat-
ment options for serious infections, increased the burden of disease, and increased
death rates due to treatment failure and requires a coordinated global response for anti-
microbial resistance surveillance. This looming health threat has restimulated interest in
the development of new antimicrobial therapies, has demanded the need for better pa-
tient care, and has facilitated heightened governance over stewardship practices.
KEYWORDS Acinetobacter, Enterobacter, Enterobacterales, Enterococcus, Klebsiella,
Pseudomonas aeruginosa, Staphylococcus aureus, antibiotic resistance, multidrug
resistance
INTRODUCTION
T he emergence of multidrug-resistant (MDR) bacteria (bacteria resistant to more

than three antibiotic classes) (1) has been paralleled by a waning antibiotic devel-
opment pipeline (2). The U.S. Centers for Disease Control and Prevention (CDC) and the
World Health Organization (WHO) categorize antimicrobial-resistant (AMR) pathogens
as a looming threat to human health (3, 4). Currently, no systematic international
surveillance of AMR exists (3), but available reports estimate that more than 2 million
AMR infections with a death toll of 29,000 occur in the United States per annum, at an
attributable health care cost of more than $4.7 billion (4). In Europe, over 33,000 deaths
and 874,000 disability-adjusted life years are attributed to hospital-acquired (HA) and
community-acquired (CA) AMR infections each year, accounting for $1.5 billion in direct
and indirect costs (5, 6). In developing nations, where economic loss estimates are not
available, communicable diseases remain the leading cause of death, and these are
now heightened by emerging and reemerging infectious diseases (7–9). While AMR
genes occur naturally in the environment, the use of antibiotics has selected for the
presence of AMR genes. The lack of rapid diagnostic methods to identify bacterial
pathogens and AMR genes in clinical settings has resulted in the often unnecessary use
of broad-spectrum antibiotics (10).
In February 2017, to focus and guide research and development related to new
antibiotics, the WHO published its list of pathogens for which new antimicrobial
development is urgently needed. Within this broad list, ESKAPE (Enterococcus faecium,
Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas
aeruginosa, and Enterobacter species) pathogens (11) were designated “priority status”
(12).
Through genetic mutation and the acquisition of mobile genetic elements (MGEs)
(13), ESKAPE pathogens have developed resistance mechanisms against oxazolidino-
nes, lipopeptides, macrolides, fluoroquinolones, tetracyclines, ␤-lactams, ␤-lactam–␤-
lactamase inhibitor combinations, and antibiotics that are the last line of defense,
including carbapenems, glycopeptides, and clinically unfavorable polymyxins (14–19).
Comparatively, resistance to lipoglycopeptides is rare and has only recently been
documented (20). This may be potentially attributed to the dual action of lipoglyco-
peptides in inhibiting both peptidoglycan synthesis and destabilizing the bacterial cell
membrane. Overall, the constitutive and/or inducible expression of these drug resis-
tance mechanisms has resulted in the increased representation of bacterial species with
these mechanisms in hospital-acquired infections (12).
Since the turn of the 1990s, the development and commercialization of novel
antibiotics have slowed. Between 2017 and 2019, 11 new antimicrobial therapies were
approved by the U.S. Food and Drug Administration (U.S. FDA) (21). Of these 11
antimicrobials, 4 were approved by the European Union European Medicines Agency
(E.U. EMA): the meropenem-vaborbactam combination (Vaborem), eravacycline (Xe-
rava), delafloxacin (Baxdela/Quofenix), and the imipenem-cilastatin-relebactam combi-
nation (Recarbrio; a positive opinion toward the granting of marketing authorization
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Antimicrobial Resistance Profiles of ESKAPE Pathogens Clinical Microbiology Reviews
was recommended in December 2019, and approval was provided in February 2020)
(22–25). Apart from these antimicrobials, during this time frame, the E.U. EMA addi-
tionally approved ceftobiprole (Zeftera; also approved by the Australian Therapeutic
Goods Agency in 2016 and by Health Canada in 2015), whereas the Japanese Pharma-
ceutical and Medical Devices Agency (PMDA) approved lascufloxacin (Lasvic) (26–29).
Global initiatives to deliver new stand-alone antibacterial therapies or complementing
alternative therapies are urgently needed. In this review, we assess the current state of
AMR in ESKAPE pathogens, with a focus on current and emerging drug development
avenues in the response against AMR.
VANCOMYCIN-RESISTANT ENTEROCOCCI
Enterococcus faecium is a prominent cause of health care-associated infections, and
hospital-adapted lineages are increasingly resistant to vancomycin (30) (Table 1). The
dissemination of Enterococcus in the United States occurred in two separate waves. The
first wave began in the 1980s and was associated with the introduction of third-
generation cephalosporins driving the emergence of vancomycin- and ampicillin-
resistant Enterococcus faecalis (31). The second wave, dominated by vancomycin-
resistant E. faecium (VREfm), was hypothesized to have spread from the United States
to other parts of the world. Several European countries have now reported increases in
VREfm prevalence in hospitalized patients (32, 33). In Australia, 47% of E. faecium blood
culture isolates are VREfm, contributing to an incidence rate of vancomycin-resistant
enterococci (VRE) which surpasses that of many other high-income nations (34, 35).
VREfm multilocus sequence types (ST) pertaining to clonal complex 17 (CC17) are
currently responsible for a significant burden of hospital-acquired infection (36). Highly
prevalent in the gut microbiome of wild and domesticated animals (37, 38), CC17
strains have been associated with outbreaks in Europe, Asia, South America, and
Australia (34, 39–42). Although the zoonotic transfer of CC17 strains from animals to
humans is largely attributed to the spread of this complex, fresh food has also been
found to be a significant reservoir (36). Despite spread in the community appearing
high, community-associated infections caused by CC17 strains are uncommon.
Compared to the durations of outbreaks caused by the other ESKAPE pathogens,
VREfm outbreaks have a long duration, approximating 11 months, on average (43, 44).
The entry of VREfm into the bloodstream of hospitalized patients is typically preceded
by antibiotic exposure, enabling VREfm to become the predominant species in the
gastrointestinal tract (45, 46). The duration of prior antibiotic exposure is strongly
associated with a subsequent risk of VRE infection (47). In a 2016 national survey of
1,058 bloodstream infections caused by Enterococcus in Australia, almost 50% of E.
faecium isolates were vancomycin resistant (48). In the United States, the incidence of
hospital- and community-acquired VRE infection between 2012 and 2017 significantly
decreased (4). The management of patients infected with VRE is complicated by the
excess cost and disruption resulting from the need for isolation rooms, contact pre-
cautions, and dedicated room cleaning. The treatment of significant infection relies
upon second-line antibiotic therapies (e.g., tigecycline and daptomycin), which are
often associated with increased cost, diminished efficacy, and a greater risk of toxicity
compared with the cost, efficacy, and risk of toxicity of first-line antibiotic therapies
(Table 1) (49, 50). Defining the additional risk of a poor outcome attributable to
vancomycin resistance in enterococci has been challenging, largely because of the
confounding effects of comorbidity (51). Most studies have demonstrated an associa-
tion of VRE infection with excess mortality, the duration of hospital admission, and
treatment costs (52, 53), especially when VRE cause a bloodstream infection (54).
METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS

Methicillin resistance was first identified in Staphylococcus aureus in 1961 as a
consequence of widespread penicillin usage (55). The introduction of penicillin also
heightened the emergence of penicillinase-producing S. aureus. Although methicillin-
resistant S. aureus (MRSA) is still a significant burden in U.S. health care settings, the

TABLE 1 Clinical characteristics of ESKAPE pathogensa
Species Resistances Clinical manifestations Major ST/CC Mortality rates Treatments Key characteristics
Vancomycin-resistant Vancomycin (184, 471), ampicillin Catheter-associated-UTI, vascular E. faecium ST17 (CC17) (35), ST203 Over 30% for bacteremia (35, 480); Nitrofurantoinb (481), fosfomycin 10% of all HA bloodstream infections (484,
Enterococcus (472), linezolid (35), catheter-associated (CC17) (475), ST796 (476), 2.5-fold increase in mortality (482), linezolid (480), 485); tolerant to heat, chlorine, and
teicoplanin (473), piperacillin bacteremia, intra-abdominal ST1421 (35), and CC17 (36); from bacteremia caused by VRE daptomycin (18), alcohol preparations (486); E. faecium
De Oliveira et al.
(474), cephalosporins (64), and pelvic infection, E. faecalis CC2 (477), CC9 (477), compared to that from chloramphenicol (483), demonstrates significantly higher levels
multidrug resistant (184) endocarditis (51) ST6 (478), and ST16 (479) bacteremia caused by doxycycline (483), high-dose of resistance than E. faecalis (35);
vancomycin-sensitive bacteria ampicillin and sulbactam commonly encountered as
(473) (483), omadacycline (396) asymptomatic colonization (487)
Methicillin-resistant Aminoglycosides (488), ␤-lactams Acute bacterial skin and skin ST5 (65), ST8 (493), ST22 (35), Greater than 20% for bloodstream Vancomycin (488), clindamycin In Asia, 50% of all S. aureus bloodstream
S. aureus (489), chloramphenicol (488), structure infection (490), ST30 (494), ST59 (495), ST72 infection (76, 77); overall (499), daptomycin (500), infections are caused by MRSA (507); in
trimethoprim (313), bacteremia (488), pneumonia (CC8) (496), ST80 (70), ST398 mortality ranges from 15–50% linezolid (501), tedizolid (502), USA, HA-MRSA infections have
macrolides (313), tetracycline (491), osteoarticular infection (livestock associated) (71, 497) (498) dalbavancin (503), tigecycline decreased by 54% (508); in Europe, the
(313), fluoroquinolones (64), (492), endocarditis (488) (504), trimethoprim and total proportion of reported MRSA
multidrug resistant (488) sulfamethoxazole (505), infections among S. aureus infections
pristinamycin (506), decreased from 19.6% in 2014 to 16.4%
July 2020 Volume 33 Issue 3 e00181-19

omadacycline (396), lefamulin in 2018 (64); 20–40% of the population
(403) carries S. aureus as a commensal
organism (488)
K. pneumoniae Polymyxins (276), carbapenems Pneumonia (510), pyogenic liver ST11 (82, 514), ST15 (82, 515), 40% to 70% for CRKP bloodstream Aminoglycosides (523), USA has more than 7,000 HA-CRKP
(509), fluoroquinolones (64), abscesses (511), necrotizing ST17 (516), ST37 (516), ST101 infection (509, 521); 40% for polymyxin combination infections per year (80); in Taiwan, 80%
third-generation and soft tissue infection (92), (82, 517), ST147 (518), ST258 CRKP pulmonary infection (521, therapy (524), tigecycline of pyogenic liver abscess cases are
cephalosporins (64), bloodstream infection, (148, 519), ST307 (88, 89), 522); 25% to 47% for hvKP (79), meropenem (523), attributed to hvKP (511)
aminoglycosides (64), meningitis (512), ST405 (520), ST512 (82) necrotizing and soft tissue meropenem-vaborbactam
tetracyclines (276), pandrug endophthalmitis (512), UTI infection (90, 92) (525), ertapenem and
resistant (276) (513) meropenem (526), imipenem-
cilastatin-relebactam (24),
ceftazidime-avibactam (527),
plazomicin (393), eravacycline
(394)
A. baumannii Carbapenems (103), polymyxins Ventilator-associated pneumonia ST195 (CC92) (531), ST457 (CC92) 35% for ventilator-associated Colistin (534), tigecycline (102), 2% of all HA-infections in USA and Europe
(108), ␤-lactams (103), (528), central line (531), pan-European epidemic pneumonia and bloodstream cefiderocol (412), eravacycline (100, 101); high mutation frequency
tigecycline (103), ceftazidime bloodstream infections (528), clones I, II, and III (532) infections (533) (394) upon desiccation (535); persistence in
(103), fourth-generation nosocomial meningitis (529), biofilms during soft tissue infection
cephalosporins (103), skin and soft tissue infection (536); tolerance to low-ethanol
multidrug resistant (101, 103) (530), catheter-associated UTI environments and resistance to
(528) chlorhexidine-based disinfectants (537,
538)
P. aeruginosa First- and second-generation UTI (540), bloodstream infection ST111 (544), ST175 (112, 544), 67% for MDR bacteremia (539); Piperacillin-tazobactam (35), High incidence of infection in burn victims
cephalosporins (110), (539), ventilator-associated ST233 (544), ST235 (111, 545), 33.9% for UTI (540) ceftolozane-tazobactam (546), (542); 51,000 HA infections in USA per
piperacillin-tazobactam (35, pneumonia (64), chronic ST253 (544), ST292 (114), ceftazidime (35), meropenem year (547–550)
110), aminoglycosides (110), respiratory infection (541), ST1725 (544) (35), ciprofloxacin (35),
quinolones (110), skin and soft tissue infection ceftazidime-avibactam (527),
carbapenems (35, 110), (542), endocarditis (543) cefiderocol (412), imipenem-
polymyxins (110), multidrug cilastatin-relebactam (24)
resistant (539)
Enterobacter species Carbapenems (3), fourth- UTI (551), bloodstream infection In K. aerogenes, ST4 (127) and Exceeds 40% for E. cloacae Nitrofurantoinb (35), cefepime E. cloacae is the 3rd most frequent
generation cephalosporins (552), neonatal pneumonia ST93 (127); in E. cloacae, ST66 bloodstream infection (552, (35), ceftriaxone (35), Enterobacterales species causing
(102), fluoroquinolones (102), (553), skin and soft tissue (557), ST78 (557), ST108 (557), 558) ciprofloxacin (35), gentamicin bloodstream infection (552); infections
␤-lactams (157), polymyxins infection (554), intra- ST144 (557), and ST171 (128) (35), meropenem (35), are prevalent in neonates and elderly
(130), multidrug resistant abdominal infection (555), piperacillin-tazobactam (35), individuals (556, 559); clinically relevant
(102), pandrug resistant (130) endocarditis (556), septic trimethoprim with or without E. hormaechei is an important emerging
arthritis (556) sulfamethoxazole (35), pathogen within the E. cloacae
imipenem-cilastatin- complex (125, 126)
relebactam (24)
aAbbreviations: ST, sequence type; CC, clonal complex; UTI, urinary tract infection; HA, hospital acquired; CRKP, carbapenem-resistant K. pneumoniae; hvKP, hypervirulent K. pneumoniae.
bNitrofurantoin is prescribed only for uncomplicated urinary tract infections.
cmr.asm.org 4
Clinical Microbiology Reviews
incidence of hospital-acquired MRSA (HA-MRSA) is declining (4, 56) (Table 1). Opposite
this finding, the incidence of community-acquired MRSA (CA-MRSA) infections in the
same region has significantly increased (56). CA-MRSA infections emerged among the
indigenous population of Australia in the 1980s (57) and in otherwise healthy commu-
nities of the United States and Canada in the 1990s (58). In North America, where
CA-MRSA is prevalent, MRSA epidemics are largely attributed to the emergence of
either of two unrelated MRSA clones (59, 60). The MRSA clone USA400, isolated from
the pediatric population, initiated the first epidemic wave and remains a common
cause of community-onset disease among indigenous populations in Alaska and the
Pacific Northwest (61). Since 2001, USA400 has been superseded by an epidemic
caused by MRSA USA300 (61, 62) and closely related variants, which are now the most
prevalent CA-MRSA isolates in North America and northern parts of South America.
Today, the burden of MRSA across the world varies substantially (4, 63, 64). In China,
the prevalence of HA- and CA-MRSA infections wavered remarkably between 2007 and
2018. The prevalence of HA-MRSA clones ST239-t030 and ST239-t037 was significantly
reduced (from 20.3% to 1% and 18.4% to 0.5%, respectively), and these have now been
replaced by the ST5-t2460 clone (from 0% to 17.3%), which has seen a rapid emer-
gence. Furthermore, the incidence of CA-MRSA clones ST59 and ST398 also increased
over the same period (from 1.0% to 5.8% and 1.8% to 10.5%, respectively) (65). In
Northern Europe (i.e., the United Kingdom and France), a steady decrease in the
prevalence of HA-MRSA was observed between 2015 and 2018 and was largely
attributed to improved national infection control programs (64, 66, 67). In comparison,
the rates of HA-MRSA in Southern Europe (i.e., Portugal, Spain, Italy, and Greece) remain
high (5, 64).
CA-MRSA strains have typically been associated with skin and soft tissue infections,
whereas HA-MRSA strains are associated with severe pneumonia and bloodstream
infections (68). The division between CA- and HA-MRSA strains is becoming indistinct,
with CA-MRSA strains now identified to be a causative agent of bloodstream infections
in nosocomial settings. MRSA ST80 is a well-defined agent of CA-MRSA in Europe.
Although it is now becoming less prevalent in select European countries (69), CA-MRSA
ST80 is now a major contributor of infection in defined health care settings (70).
Furthermore, examples of CA-MRSA (e.g., ST398) have been shown to be associated
with exposure to livestock (particularly pigs) in Europe (71) (Table 1). Although indi-
viduals with direct exposure to livestock are the most at risk from livestock-associated
MRSA (LA-MRSA), it has now been reported that LA-MRSA substantially contributes to
the burden of nosocomial infection in Europe (72). One of the less-defined and
neglected subgroups of S. aureus is borderline oxacillin-resistant S. aureus (BORSA).
Found both in community settings and in hospital settings, BORSA is characterized by
intermediate resistance to penicillinase-resistant penicillins, with oxacillin MICs being
between 1 and 8 ␮g/ml (73). Lacking the mecA gene, BORSA is not truly either
methicillin resistant or methicillin sensitive, and frequent misidentification poses a
significant threat to patient treatment and outcome, as severe BORSA infections may be
nonresponsive to high doses of oxacillin (74). Overall, MRSA infections carry additional
health care burdens in terms of morbidity, length of hospital stay, health care costs, and
quality of life (75). The rate of mortality following S. aureus bloodstream infection
exceeds 20%, and the presence of methicillin resistance is independently associated
with increased mortality (76, 77).
KLEBSIELLA PNEUMONIAE
Cephalosporin- and carbapenem-class antibiotics have been a mainstay of treat-
ment for serious infections caused by Enterobacterales, such as K. pneumoniae, but
efficacy has been compromised by the widespread acquisition of genes encoding
enzymes, such as extended-spectrum ␤-lactamases (ESBLs) and carbapenemases,
which mediate the respective resistance to these critical drugs (19). High rates of
mortality, often exceeding 40%, have been associated with severe infections caused by
carbapenem-resistant Enterobacterales (CRE) (78). Effective antimicrobial options are

often lacking, and treatment typically requires reliance on drugs with a risk of toxicity
(e.g., aminoglycosides, polymyxins) or other safety concerns (e.g., tigecycline) (79)
(Table 1). Carbapenem-resistant K. pneumoniae (CRKP) strains are the most clinically
prominent CRE (64, 80). In the United States, carbapenemases carried by K. pneumoniae
were originally reported in 2001 (81). Since then, the genes encoding these
␤-lactamases have spread among several Gram-negative bacterial species. Between
2005 and 2010, an increase in CRKP isolates causing invasive infections was reported
across Europe (64). The spread of CRKP in Europe has been driven by direct and indirect
patient-to-patient transmission in nosocomial settings, largely attributed to ST11, ST15,
ST101, and ST258 strains, along with the ST258 derivative ST512 (82) (Table 1). The
global burden of CRKP has now been further exacerbated by successive waves of CRKP
emerging from several locations across the Indian Ocean rim, the United States, and
China (83–87). The global dissemination of CRKP is exemplified by the CRKP clone
ST307. The ST307 clone has successfully disseminated across every major continent
(88), demonstrating extremely high transmission rates in health care settings (89).
Recent reports suggest that AMR hypervirulent K. pneumoniae (hvKP) strains are also
emerging. In Taiwan, hvKP causes as many cases of necrotizing fasciitis as Streptococcus
pyogenes and is associated with a higher mortality rate (47% versus 19%) (90). The
detection of hvKP is now being reported around the world in both high- and low-
income settings (87, 91, 92). An important laboratory feature frequently seen in hvKP
strains is the presence of a hypermucoviscous phenotype (in association with the K1
and K2 capsular serotypes) (93).
ACINETOBACTER BAUMANNII
A. baumannii infections typically occur in hospitalized patients or patients with
significant contact with the health care system (94). Historically, A. baumannii has been
associated with hot and/or humid geographic climates (95, 96). Between 1987 and
1996, the frequency of both community- and hospital-acquired infections across the
United States was observed to rise by 50% between the months of July and October
(97). Since the 1970s, A. baumannii has become increasingly common in temperate
climates, a shift largely attributed to improved environmental persistence mechanisms
and MDR development (98). Community-acquired pneumonia due to A. baumannii has
been described in tropical regions of Asia and Australia among individuals with a
history of alcohol abuse (99). Although A. baumannii infection rates are comparatively
low compared to those of other ESKAPE pathogens (100, 101), approximately 45% of all
global A. baumannii isolates are considered MDR, with rates exceeding 60% in the
United States (4, 101), Latin America, and the Middle East (102). Turkey and Greece have
reported MDR rates exceeding 90% (103). These levels of MDR for A. baumannii are over
four times higher than those observed in K. pneumoniae and P. aeruginosa (3). A key
aspect of A. baumannii physiology is the propensity to develop rapid resistance. From
2011 to 2016, the rate of identification of A. baumannii isolates resistant to
carbapenem- and ␤-lactam-class antibiotics has increased by over 30% globally (103).
The spread of MDR and carbapenem-resistant A. baumannii (CRAB) isolates is largely
associated with three international clonal lineages: CC1, CC2, and CC3 (104, 105). CC1
is prevalent worldwide, while CC2 and CC3 are highly prevalent in Europe and North
America. CC15 and CC79 are also predominant in Central and South America (106, 107).
With the emergence of pandrug-resistant isolates, last-resort carbapenem- and
polymyxin-class antibiotics are no longer effective (103, 108) (Table 1). Without ade-
quate action via improved epidemiological surveillance and therapeutic development,
A. baumannii has the capacity to potentiate a global epidemic.
PSEUDOMONAS AERUGINOSA
Widely present in aquatic environments, P. aeruginosa is a Gram-negative opportu-
nistic human pathogen commonly associated with severe respiratory infections in
patients with impaired immunity. While P. aeruginosa is responsible for 10% of all

nosocomial infections, there is also increasing acknowledgment of P. aeruginosa as a

cause of community-acquired infection.
The plasticity and adaptability of the P. aeruginosa genome, conferred by a reper-
toire of regulatory genes (⬎8% of the 6-Mb genome), are key features in the pathogen’s
ability to chronically persist in the host and evade antibiotic treatment (109). Intrinsi-
cally resistant to a wide array of antimicrobial agents, P. aeruginosa currently displays
resistance to multiple classes of antibiotics (6, 110) (Table 1). In the United States,
although AMR rates remain high, surveillance suggests a trend toward declining rates
of resistance (4). Globally, patterns of P. aeruginosa AMR vary substantially. Today, the
highest rates of AMR in P. aeruginosa occur in North, Central, and South America,
Western and Central Europe, China, India, and Southeast Asia (7). With an enhanced
capacity to acquire and maintain foreign antibiotic resistance elements, P. aeruginosa
lineages ST235 and ST175 have emerged as high-risk globally dispersed clones and
remain a major contributor of hospital-acquired infection (111, 112). Furthermore, the
widespread distribution of P. aeruginosa nosocomial isolates resistant to last-resort
polymyxin- and carbapenem-class antibiotics is well documented (7, 113, 114).
Patients with chronic or inherited lung disease, such as bronchiectasis and cystic
fibrosis (CF), are highly susceptible to persistent pulmonary infection, with episodic
exacerbations requiring hospitalization and intravenous antibiotics, with a subsequent
risk of selection for MDR (115). P. aeruginosa has been shown to remain viable in the
lungs of patients diagnosed with CF for over a decade (116). P. aeruginosa colonizes
moist environments and therefore can be found in many health care settings, especially
in the context of chronic wounds, respiratory support, or urinary tract devices, where
biofilm formation predisposes for persistence, immune evasion, and antimicrobial
resistance (117, 118).
ENTEROBACTER SPECIES
Over the last 35 years, Enterobacter aerogenes (now renamed Klebsiella aerogenes)
and Enterobacter cloacae species have presented as significant threats to neonatal
wards and patients in intensive care units, particularly those dependent on mechanical
ventilation (119). The emergence of these two Enterobacter species as clinically signif-
icant MDR pathogens has occurred in concurrent epidemic waves. From the early 1990s
to 2003, E. aerogenes was the most clinically prevalent cause of Enterobacter nosocomial
infection (119). During this period, the hospital-acquired E. aerogenes infection inci-
dence was high in Western Europe (120, 121), largely attributed to the dispersion of a
single epidemic clone (122, 123). In about 2010, E. aerogenes was superseded by E.
cloacae as the most common clinically isolated species of the genus (124). It is worth
noting that other members of the E. cloacae complex, especially Enterococcus hormae-
chei, are clinically relevant and are often difficult to discriminate at the species level
based on standard phenotypic assays (125, 126).
MDR Enterobacter species are an increasing cause of hospital-acquired infection. In
the United States, E. aerogenes ST4 and ST93 currently represent prevalent lineages
associated with nosocomial infection (127). For the E. cloacae complex, recent data
suggest that carbapenem resistance has directionally spread across the United States
due to the dissemination of hospital-associated carbapenem-resistant E. cloacae ST178
and ST78 isolates (128). Prior to 2005, an estimated 99.9% of Enterobacter strains were
sensitive to carbapenems (129). Carbapenem resistance is now reported in all WHO
health regions (3). Moreover, pandrug-resistant E. aerogenes has also emerged, display-
ing resistance to the last-resort antibiotic colistin (130) (Table 1). To complicate the
treatment of bacterial infections further, E. aerogenes is capable of harboring subpopu-
lations of colistin-resistant bacteria which are undetectable using current diagnostic
testing strategies (131).
ESCHERICHIA COLI
Although not formally recognized as part of the ESKAPE group of pathogens, AMR
Escherichia coli is identified as a major cause of bloodstream and urinary tract infection

(UTI) in both community and health care settings globally (5, 35, 64). Sepsis is one of
the most common manifestations of E. coli UTI. In Australian inpatient and emergency
department settings, E. coli is the most prevalent Gram-negative bacterial species
isolated from both blood and urine cultures (35). Over the past decade, several
pandemic clones of MDR uropathogenic E. coli (e.g., ST131 and ST95) have dissemi-
nated worldwide (132, 133). Through horizontal gene transfer, E. coli typically acquires
resistance genes from other members of the Enterobacterales. High rates of resistance
to aminopenicillins, fluoroquinolones, aminoglycosides, and third-generation cephalo-
sporins are noted across Europe (64). Although carbapenem resistance is rare in
invasive E. coli strains, the general situation in Europe for CRE, including E. coli, was
shown to worsen between 2010 and 2018 (134). Furthermore, in 2016, resistance to the
last-resort polymyxin, colistin, was identified in E. coli strains isolated from pig farms in
China (135). Although not discussed further in this review, AMR E. coli is currently one
of the largest clinical burdens facing both human and animal health. In order not to
exacerbate these challenges further, organizations involved in AMR policy, research and
development (R&D), and surveillance need to consider this pathogen as a critical public
health concern.
ESKAPE PATHOGEN MECHANISMS OF ANTIBIOTIC RESISTANCE

Given the frequency at which ESKAPE organisms are encountered in the clinical
setting, it is not surprising that numerous different AMR mechanisms are observed in
these pathogens. These can be broadly categorized into four groups, comprising (i)
inactivation or alteration of the antimicrobial molecule, (ii) bacterial target site modi-
fications, (iii) reduced antibiotic penetration/accumulation, and (iv) the formation of
bacterial biofilms (Fig. 1). Here we explore the most important AMR determinants that
have contributed to the success of ESKAPE pathogens in the modern-day clinical
setting.
Antibiotic Inactivation/Alteration
One of the most common AMR mechanisms employed by ESKAPE pathogens
involves the production of enzymes that irreversibly destroy or neutralize antibiotics.
Such enzymes are particularly prevalent among the Gram-negative pathogens and
comprise those (i) that destroy the active antibiotic site (e.g., hydrolytic cleavage of the
␤-lactam ring by ␤-lactamases) or (ii) that covalently modify key structural elements of
the drug to hinder bacterial target site interaction (e.g., aminoglycoside-modifying
enzymes [AMEs] that catalyze hydroxyl/amino group modifications).
␤-Lactamases. ␤-Lactamase enzymes were first identified soon after the initial
discovery and purification of penicillin (136). Since then, ⬎2,600 unique ␤-lactamases
enabling resistance to one or more ␤-lactams (i.e., penicillins, cephalosporins, mono-
bactams, and carbapenems) have been described (137). ␤-Lactamases remain the most
important resistance mechanism among Gram-negative ESKAPE pathogens, where they
are concentrated within the periplasm, thus hydrolyzing the ␤-lactam agents prior to
reaching the penicillin-binding protein (PBP) target in the cell wall.
␤-Lactamase enzymes are typically classified according to their primary molecular
structure (i.e., the Ambler scheme [138]) or combined hydrolytic and inhibition func-
tional properties (i.e., the Bush-Jacoby system [139]). Ambler class A enzymes contain
serine in their active site and comprise penicillinases, cephalosporinases, narrow- and
broad-spectrum ␤-lactamases, extended-spectrum ␤-lactamases (ESBLs), and carbap-
enemases. Overall, they represent the largest cluster of ␤-lactamase enzymes and
collectively are capable of inactivating most ␤-lactam classes, including the penicillins,
early cephalosporins, third-generation oxyimino-cephalosporins, monobactams, cepha-
mycins, and carbapenems. Their susceptibility to inhibition by clavulanic acid and
tazobactam is variable, though all are inhibited by novel ␤-lactamase inhibitor agents,
including avibactam, relebactam, and vaborbactam (139, 140).
Ambler class A enzymes comprise various important ␤-lactamases that are fre-
quently observed in Gram-negative (e.g., TEM, SHV, CTX-M, and KPC) and Gram-positive

FIG 1 Mediators of ESKAPE pathogen antimicrobial resistance. Mechanisms facilitating antimicrobial resistance in ESKAPE pathogens can be broadly categorized
into four groups: (i) enzyme-mediated antimicrobial inactivation, which either irreversibly destroys the active antibiotic site (e.g., hydrolytic cleavage of the
␤-lactam ring by ␤-lactamases) or covalently modifies key structural elements of the drug to hinder the bacterial target site interaction (e.g., aminoglycoside-
modifying enzymes that catalyze hydroxyl/amino group modifications); (ii) bacterial target site modification, which prevents the binding or which reduces the
affinity of the antibiotic molecule at the cell surface (e.g., LPS modification, PBP2a expression with reduced ␤-lactam affinity, and van gene cluster-mediated
peptidoglycan modification) or intracellularly (e.g., 16S RNA methylation); (iii) reduced antibiotic accumulation through the mutation or loss of outer membrane
channels (e.g., OprD in P. aeruginosa, CarO in A. baumannii, and OmpK36 in K. pneumoniae) and expression of efflux systems to actively extrude drugs out of
the cell (e.g., RND, MFS, MATE, SMR, ABC, and PACE); and (iv) persistence through biofilm-embedded cells which demonstrate a markedly higher tolerance to
antimicrobial agents than planktonic bacteria. AMEs, aminoglycoside-modifying enzymes; AACs, aminoglycoside acetyltransferases; ANTs, aminoglycoside
nucleotidyltransferases; APHs, aminoglycoside phosphotransferases; LPS, lipopolysaccharide; PBP, penicillin-binding protein; RND, resistance-nodulation-
division; MFS, major facilitator superfamily; MATE, multidrug and toxic compound extrusion; SMR, small multidrug resistance; ABC, ATP-binding cassette; PACE,
proteobacterial antimicrobial compound efflux; EPS, extracellular polymeric substance.
(e.g., penicillinase) ESKAPE pathogens. Indeed, blaZ-encoded penicillinases that

emerged widely and soon after the introduction of penicillin are now detectable in
⬃85% of clinically significant S. aureus isolates and some Enterococcus spp. (141–144).
Likewise, the narrow-spectrum TEM-type ␤-lactamases, which readily hydrolyze early
cephalosporins and penicillins, are frequently encountered in K. pneumoniae and
Enterobacter spp. but have also been reported in A. baumannii and P. aeruginosa. SHV-1,
which has a substrate and inhibition profile similar to that of TEM-1, is almost univer-
sally found in the progenitor species, K. pneumoniae (144, 145).
Due to a combination of strong selection pressures and the frequency at which AMR
determinants are mobilized between organisms, both TEM- and SHV-type enzymes
have undergone extensive evolution in recent decades (145). This has resulted in the
proliferation and dissemination of numerous plasmid-encoded ESBL variants that can
also hydrolyze oxyimino-␤-lactams and aztreonam (139, 145). Other class A ESBLs,
namely, enzymes of the CTX-M, PER, GES, and VEB families, have also been reported
across all Gram-negative ESKAPE pathogens. Characteristically, most class A ESBL

enzymes remain susceptible to clavulanic acid, though Bush-Jacoby subgroup 2br and
2ber ESBLs (e.g., TEM-30, SHV-10, and TEM-50) show reduced susceptibility to various
␤-lactamase inhibitors (146). Concerningly, inhibitor-resistant ␤-lactamases have also
been reported in K. pneumoniae strains harboring KPC serine carbapenemase enzymes
(147). Plasmid-encoded KPCs have been associated with major outbreaks worldwide (e.g.,
the outbreak caused by K. pneumoniae ST258) and hydrolyze virtually all ␤-lactams,
including carbapenems (148). Despite this, there is emerging evidence that infections with
KPC-producing organisms can be successfully targeted with various new ␤-lactamase–␤-
lactamase inhibitor combinations, including imipenem-cilastatin-relebactam, meropenem-
vaborbactam, and ceftazidime-avibactam (149). Unfortunately, the rapid evolution of
ceftazidime-avibactam resistance has already been reported in K. pneumoniae ST258
blaKPC-3-harboring isolates and in non-ST258 clonal backgrounds and additional blaKPC
variants (17, 150, 151).
Ambler class B metallo-␤-lactamases (MBLs) represent another clinically important
group of enzymes capable of hydrolyzing most ␤-lactams, including carbapenems.
However, in contrast to other ␤-lactamases, they require Zn2⫹ at their active site,
display a low affinity for aztreonam, and are inhibited by EDTA (139). The most
prominent MBLs encountered in the Gram-negative ESKAPE pathogens (e.g., MBLs of
the IMP, VIM, and NDM families) are encoded on conjugative plasmids. IMP- and
VIM-type MBLs were first detected in clinical P. aeruginosa isolates (152, 153) but have
since been identified in K. pneumoniae, E. cloacae complex isolates, and Acinetobacter
spp. (154–157). NDM-type enzymes have also been detected across all Gram-negative
ESKAPE bacteria and are of particular concern due to the fact that they are incorporated
into transferable genetic elements that also encode determinants for resistance to
other antibiotic classes (157, 158).
Group C ␤-lactamases comprise chromosomally encoded cephalosporinases, such
as AmpC, that are found in many Enterobacterales (including Enterobacter spp.), P.
aeruginosa, and Acinetobacter spp. (159). They are most active on narrow- to
intermediate-spectrum cephalosporins plus aztreonam and are usually resistant to
clavulanic acid. The rate of constitutive expression of AmpC is usually low, but clinically
relevant resistance is inducible during therapy (139). Plasmid-mediated resistance
involving group C enzymes has also been reported widely, including reports of plas-
mids in organisms, such as K. pneumoniae, that do not normally contain genes
encoding these enzymes on their chromosome (159).
␤-Lactamases belonging to Ambler class D primarily consist of oxacillin-hydrolyzing
enzymes (OXA), which are able to hydrolyze oxacillin and its derivatives, which display
ESBL-like substrate properties, and which show variable resistance to ␤-lactam inhibi-
tors (139). Importantly, some OXA-type ␤-lactamases, such as OXA-48 and its deriva-
tives, also confer carbapenem resistance. OXA-type enzymes are most frequently found
in Acinetobacter spp., where they are often located on the chromosome. However,
plasmid-borne OXA-48-like enzymes are now widely distributed in many Enterobacte-
rales species, including K. pneumoniae and Enterobacter spp. (160), many of which
express other ESBLs, such as CTX-M-15, and thus provide resistance to most ␤-lactam
agents (161).
Aminoglycoside-modifying enzymes. The most common aminoglycoside resis-
tance mechanism encountered among ESKAPE pathogens occurs through the produc-
tion of AMEs. During transportation of the drug across the cytoplasmic membrane,
these enzymes covalently catalyze specific hydroxyl or amino group modifications of
the aminoglycoside molecule, thus reducing antibacterial activity through diminished
bacterial ribosomal subunit binding. Based on their biochemical activity, there are three
classes of AMEs (i.e., aminoglycoside acetyltransferases [AACs], aminoglycoside phos-
photransferases [APHs], and aminoglycoside nucleotidyltransferases [ANTs]). Enzymes
within each class are then further subdivided according to the position of the modifi-
cation site, resistance profile, and specific protein designation (162). Earlier work has
shown that the global distribution of AMEs varies with respect to geography, antibiotic
selection pressure, and bacterial species (163, 164). Depending on the specific enzyme

and the host organism, genes coding for AMEs are located on plasmids, on transposons,
or in the chromosome (162), though the high frequency of these resistance determi-
nants among ESKAPE pathogens is largely attributable to acquisition via horizontal
gene transfer (165).
AACs encompass the largest AME class and in an acetyl coenzyme A-dependent
manner catalyze the acetylation of specific amino groups present on the antibiotic
acceptor molecule. Of the four AAC subclasses, the AAC(1) and AAC(3) enzymes target
amino group positions 1 and 3 of the central 2-deoxystreptamine ring, respectively,
whereas the AAC(2=) and AAC(6=) subclasses modify the respective 2= and 6= amino
group positions of the 2,6-dideoxy-2,6-diamino-glucose ring (166). While comprehen-
sive analyses of global AAC epidemiology remain relatively scarce, recent investigations
conducted in the United States, Europe, and Asia indicate that Gram-negative ESKAPE
pathogens most frequently encode AAC(3) and AAC(6=) enzymes, which collectively
confer resistance to gentamicin, tobramycin, and amikacin (165, 167, 168).
APHs comprise the second most abundant class of AMEs, which decrease aminogly-
coside binding affinity by catalyzing ATP-dependent phosphorylation of —OH groups
on the antibiotic molecule. Of the seven different APH subclasses [i.e., APH(4), APH(6),
APH(9), APH(3=), APH(2⬙), APH(3⬙), and APH(7⬙)], APH(3=) is the most widely distributed
among clinical isolates, with the aph(3=)-IIIa gene being recognized as a key determi-
nant of plasmid-mediated amikacin resistance in both S. aureus and Enterococcus spp.
(165).
The final class of AMEs encompasses the ANTs, which reduce aminoglycoside
toxicity via the magnesium-dependent transfer of a nucleoside monophosphate
to —OH groups on the antibiotic molecule. Overall, there are five subclasses of ANTs
[i.e., ANT(6), ANT(9), ANT(4=), ANT(2⬙), and ANT(3⬙)], of which ANT(4=) and ANT(2⬙) are
the most clinically relevant. ANT(4=) enzymes conferring resistance to amikacin and
tobramycin have been detected in S. aureus, Enterococcus spp., K. pneumoniae, and P.
aeruginosa. ANT(2⬙), encoded by the ant(2⬙)-Ia (or aadB) gene, is frequently associated
with gentamicin and tobramycin resistance across all the Gram-negative ESKAPE
organisms (165).
Most importantly, broad-spectrum aminoglycoside resistance in the ESKAPE patho-
gens is often conferred through the presence of multiple or bifunctional AMEs. This
frequently occurs among Gram-negative organisms, where multiple AMEs result in
significantly increased aminoglycoside resistance (169–171). Likewise, expression of the
bifunctional AAC(6=)-APH(2⬙) enzyme, which resides on the common Tn4001 trans-
poson, accounts for high-level gentamicin resistance in both S. aureus and Enterococcus
spp. (including MRSA and VRE strains) worldwide (152). More recently, a variant enzyme
termed AAC(6=)-Ib-cr, which confers low-level plasmid-mediated aminoglycoside and
ciprofloxacin resistance, has been described in K. pneumoniae, Enterobacter spp., A.
baumannii, and P. aeruginosa (172–175).
Target Site Modifications

Another common AMR strategy employed by the ESKAPE pathogens is to modify
the antibiotic target site, thereby reducing the affinity or preventing the binding of the
antibiotic molecule. Specifically, these mechanisms include (i) target enzyme modifi-
cation, (ii) ribosomal target site alterations, and (iii) cell wall precursor alterations.
Target enzyme modifications. ␤-Lactam antibiotics inhibit bacteria by binding to
PBP enzymes anchored in the cell wall. In MRSA, resistance to methicillin and other
␤-lactam antibiotics is mediated through expression of the foreign mecA gene. mecA
codes for PBP2a, a modified PBP with a low affinity for ␤-lactams, which renders most
␤-lactam agents completely ineffective against MRSA (176). mecA is located within the
staphylococcal cassette chromosome mec (SCCmec), which also encodes a two-
component regulatory system (TCRS; designated MecI and MecR1), site-specific ccr
recombinase genes, as well as three joining (J) regions that can contain additional
resistance determinants, mobile genetic elements (MGEs), and regulators (176). Cryptic
or low-level mecA-positive MRSA strains displaying oxacillin MICs of ⱕ2 ␮g/ml are often

misidentified as methicillin-sensitive S. aureus, proving a particular problem in the

accurate identification of CA- and LA-MRSA (177, 178).
Thirteen distinct SCCmec types of various sizes and with various genetic contents
have been identified thus far in S. aureus (179). Isolates possessing multidrug resistance
and larger SCCmec types are typically associated with hospital-acquired MRSA (HA-
MRSA) strains (e.g., SCCmec types I to III), whereas community-acquired strains express-
ing predominantly ␤-lactam resistance alone are more often associated with smaller
SCCmec cassettes (e.g., types IV and V). Interestingly, two other mec gene homologues
(designated mecB and mecC) have been recently identified in MRSA (180, 181). Though
the frequency of strains expressing mecB is unclear at present, recent studies indicate
that mecC-encoding S. aureus strains are predominantly found across the United
Kingdom and Europe at a low but variable prevalence across several host species,
including livestock and humans (176, 182, 183).
Both E. faecalis and E. faecium also express PBP5, a low-affinity chromosomally
encoded ortholog of PBP2a in MRSA, which confers intrinsic low- to moderate-level
␤-lactam resistance (penicillin MICs are 2 to 8 ␮g/ml for E. faecalis and 16 to 32 ␮g/ml
for E. faecium). In addition, up to 90% of hospital-associated E. faecium strains show
high-level ampicillin resistance (MICs, ⬎128 ␮g/ml), arising through the overproduction
of PBP5 or polymorphisms in PBP5, which further decrease the affinity for ␤-lactam
agents (184, 185). Although uncommonly reported, alterations in A. baumannii PBPs
can also contribute to carbapenem resistance (186).
Another important example in which AMR arises in ESKAPE pathogens through
modification of enzyme targets is fluoroquinolone resistance. Fluoroquinolones, such as
ciprofloxacin and norfloxacin, represent some of the most widely prescribed antimi-
crobial agents worldwide. These are active against most ESKAPE organisms and target
the DNA gyrase and topoisomerase IV enzymes, necessary for bacterial DNA repair and
replication. Each of these heterotetrameric topoisomerases consists of two pairs of
subunits (A and B) encoded by the gyrA and gyrB genes, respectively (or the parC and
parE topoisomerase IV homologues, respectively) (187). Fluoroquinolone resistance
most commonly occurs through spontaneous gyrA and parC mutations that give rise to
amino acid changes clustered in the 5= quinolone-binding region of the enzyme
(188–190), though there is some evidence to suggest that B-subunit alterations also
contribute to reduced susceptibility (191, 192). The level of resistance achieved by
single-target mutations is dependent on both the specific agent and the bacterial
species (187), while the accumulation of multiple mutations across both target enzymes
often leads to the evolution of a high-level fluoroquinolone resistance phenotype (193).
Plasmid-mediated quinolone resistance (PMQR) conferred by Qnr-family proteins
represents another fluoroquinolone resistance mechanism in K. pneumoniae and En-
terobacter spp. (194, 195). qnr-encoded proteins (e.g., QnrA, QnrB, QnrS) bind directly to
the DNA gyrase antibiotic target, thereby providing low-level fluoroquinolone resis-
tance. PMQR is common among ESBL-producing organisms and can augment fluoro-
quinolone resistance levels arising through other mechanisms (194, 195).
Ribosomal target site alterations. A major mechanism of resistance to macrolide-
lincosamide-streptogramin B (MLSB) antibiotics in S. aureus and Enterococcus spp. is
mediated by the erm-encoded rRNA methyltransferases. These enzymes mono- or
dimethylate the A2058 residue within the 23S rRNA of the bacterial 50S ribosomal
subunit, thus impairing MLSB target binding (196, 197). Expression of erm can be either
constitutive or inducible. Constitutively expressing strains display cross-resistance to all
MLSB agents. In contrast, inducibly resistant strains show resistance to 14- and 15-
member inducer macrolides (e.g., erythromycin, clarithromycin, and azithromycin) but
remain susceptible to lincosamides and streptogramin. There are 42 currently described
classes of erm genes, many of which are located on mobile genetic elements (MGEs).
erm(A) resides on transposon Tn554 as part of the SCCmec II cassette found predom-
inantly in HA-MRSA strains. erm(C) is primarily associated with plasmid-mediated
resistance in methicillin-susceptible S. aureus, whereas erm(B) is more commonly
found in enterococci (198, 199).

ESKAPE organism resistance to linezolid and aminoglycosides is also mediated at the

ribosomal level. Indeed, linezolid resistance in both S. aureus and Enterococcus spp. can
arise through mutations in genes encoding 23S rRNA and/or 50S ribosomal subunit
proteins or via Cfr-mediated methylation of 23S rRNA at residue A2503 (200). The cfr
gene is transferable within MGEs, often in association with other AMR determinants
(e.g., erm) (201, 202), and has been detected in staphylococcal strains possessing other
linezolid resistance mechanisms (203). The enzymatic methylation of 16S rRNA confer-
ring high-level aminoglycoside resistance (to all aminoglycosides, including plazomicin
[described below]) has also recently emerged as an important acquired AMR mecha-
nism in the Gram-negative ESKAPE pathogens (204, 205). To date, 10 different classes
of 16S rRNA methyltransferases have been documented worldwide (e.g., ArnA, RmfA to
RmfH, and NmpA). Concerningly, these enzymes are often located on plasmids that
harbor the genes for other MDR determinants (e.g., blaOXA-23 and blaNDM), thus further
reducing the available treatment options (205).
Cell wall precursor alterations. One of the most important AMR mechanisms that
has emerged in Gram-positive ESKAPE organisms in recent decades has been the
development of glycopeptide resistance. In susceptible Gram-positive organisms, bac-
terial cell wall biosynthesis is inhibited by glycopeptides that target outer cell wall
D-Ala–D-Ala peptidoglycan precursor residues. Glycopeptide resistance in enterococci
involves the acquisition of van gene clusters which coordinate (i) the synthesis of
modified peptidoglycan precursors that exhibit subdued glycopeptide binding (i.e., the
natural D-Ala–D-Ala termini are replaced with either D-Ala-D-lactate or D-Ala–D-serine)
and (ii) the production of D,D-carboxypeptidases that eliminate residual natural D-Ala–
D-Ala precursors from the host cell (184, 206). To date, nine distinct van gene clusters
have been classified, with the majority of human VRE infections being attributed to E.
faecium and E. faecalis isolates carrying vanA and vanB gene clusters. vanA-mediated
resistance occurs most frequently and is characterized by high-level resistance to both
vancomycin and teicoplanin (206). The vanA gene cluster is typically associated with
Tn1546 and related transposons, which can be localized on both plasmids and chro-
mosomal DNA (207). In contrast, the vanB gene cluster confers resistance to only
vancomycin and is most often carried by Tn1547/Tn5382 transposons that localize to
the chromosome (208, 209).
Since 2002, sporadic cases of vancomycin-resistant S. aureus (termed VRSA) infection
have also been reported. This form of vancomycin resistance (MIC, ⱖ16 ␮g/ml) is
conferred by the vanA gene cluster on Tn1546, which is acquired via conjugative
transfer of enterococcal plasmids (210, 211). In such instances, vancomycin resistance
is maintained either by retention of the donor enterococcal plasmid within the S. aureus
recipient or through transposition of the incoming Tn1546 element onto an endoge-
nous staphylococcal plasmid. Most cases of VRSA infection have been observed among
patients with prior/current VRE infections, though the frequency of such detections is
low, with less than 20 cases being reported across North America, South America, and
Europe to date (212–215). This most likely reflects several factors, including plasmid
instability, the relatively low prevalence of donor Enterococcus strains containing
compatible plasmids carrying vanA, robust S. aureus restriction modification systems
which restrict unmodified DNA from entering the cell, as well as VanA-associated fitness
costs (216–219).
A much more commonly encountered issue is the detection of S. aureus isolates that
exhibit intermediate resistance to vancomycin (i.e., MICs, 4 to 8 ␮g/ml; termed
vancomycin-intermediate S. aureus [VISA] strains). This form of AMR typically emerges
through prolonged exposure to vancomycin, giving rise to an initial heterogeneous
VISA (hVISA) phenotype, in which a small subpopulation of cells demonstrates MICs
of ⱖ4 ␮g/ml (220). The precise mechanisms underlying the hVISA/VISA phenotypes are
incompletely understood, though various studies indicate the role of genetic modifi-
cations to regulatory genes and global epigenetic changes which lead to cell wall
thickening, decreased peptidoglycan cross-linking, and autolytic activity, as well as an
excess of D-Ala–D-Ala residues (198, 221–225). As opposed to person-to-person trans-

mission, the vast majority of hVISA and VISA infections arise via in vivo evolution within
individual patients and typically involve pandemic HA-MRSA lineages (e.g., ST239 and
ST5). However, it should be noted that CA-MRSA clones, including the USA300 clone,
can also exhibit this resistance phenotype (146, 226).
Resistance to daptomycin, an agent that has activity against Gram-positive bacteria
and that is related to host cationic antimicrobial peptides (AMPs), has also been
observed in both S. aureus and enterococci in recent years. The precise mechanisms of
resistance are yet to be fully elucidated, but it has been postulated that alterations in
cell surface charge, phospholipid composition/metabolism, and membrane stress re-
sponses are involved (227). Recent studies also highlight the emergence of acquired
polymyxin (another cationic AMP) resistance in K. pneumoniae, A. baumannii, and P.
aeruginosa arising from remodeling of outer membrane (OM) lipopolysaccharide (LPS)
lipid A structures. These modifications contribute to reduce the net negative charge of
the LPS, thus reducing its polymyxin binding efficiency. In K. pneumoniae, loss-of-
function mutations of the mgrB gene (a negative feedback regulator of the PhoPQ
TCRS), mutations driving the expression of the PhoPQ, PmrAB, and CrrAB TCRS, as well
as the acquisition of the plasmid-mediated mcr gene all give rise to resistance-
associated lipid A modifications (e.g., addition of 4-amino-4-deoxy-L-arabinose [Ara4N],
phosphoethanolamine [PEtN], and 2-hydroxymyristate through increased expression of
the pmrHFIJKLM operon, pmrC, and lpxO, respectively) (135, 228–230). Of these, mgrB
inactivation has been reported the most frequently and, interestingly, also gives rise to
other modifications that collectively promote virulence and that attenuate early host
defense responses (228). The primary mechanisms of polymyxin resistance in A. bau-
mannii comprise mutations in the PmrAB TCRS leading to PEtN synthesis and the loss
of LPS through inactivation of the lpxA, lpxC, and lpxD lipid A biosynthesis genes (229).
Polymyxin resistance in P. aeruginosa is conveyed by five TCRS, including PmrAB,
PhoPQ, ParRS, ColRS, and CpsRS, most frequently resulting in the constitutive expres-
sion of pmrHFIJKLM and the addition of Ara4N (229).
Reduced Antibiotic Penetration and Accumulation

Porins. Mutations leading to the downregulation, balance, function, and/or loss of
the outer membrane protein channels (porins) also represent important mediators
of AMR among Gram-negative ESKAPE pathogens. Hydrophilic agents, such as the
␤-lactams (including carbapenems) and some fluoroquinolones which rely on porins to
penetrate the outer membrane barrier, are particularly affected. Moreover, these mu-
tations can arise during treatment (231, 232) and, importantly, enhance the influence
of other resistance mechanisms, such as efflux pumps and degradative enzymes (198).
For example, the loss or modification of the P. aeruginosa OprD porin is linked to
reduced carbapenem susceptibility (233). Likewise, the loss or inactivation of CarO in A.
baumannii is associated with imipenem resistance (234). During antibiotic therapy, it is
also recognized that K. pneumoniae and some Enterobacter spp. can sequentially alter
the balance of different porins. In some cases, the sorbitol-sensitive Omp35 porin is
replaced with Omp36, which has a smaller channel size. These Omp35-deficient,
Omp36-producing strains typically exhibit intermediate carbapenem susceptibility pro-
files, while those lacking both porins show carbapenem resistance (233, 235, 236).
Overexpression of the LamB porin in association with strains showing porin deficiency
or reduced porin expression can also contribute to reduce ␤-lactam susceptibility (235,
236). Mutations leading to conformational changes in the eyelet region of the E.
aerogenes Omp36 lumen with reduced ␤-lactam permeability have also been reported
(235).
Efflux pumps. The expression of bacterial efflux pumps, which actively extrude
drugs out of the cell, also greatly contributes to AMR. Genes encoding efflux pumps can
be located on the chromosome or within MGEs. To date, six major families of efflux
pumps have been characterized, comprising the (i) resistance-nodulation-division
(RND), major facilitator superfamily (MFS), multidrug and toxic compound extrusion
(MATE), small multidrug resistance (SMR), ATP-binding cassette (ABC), and proteobac-

terial antimicrobial compound efflux (PACE) families (234, 237). All six families are
represented within the ESKAPE group, with individual exporters varying in terms of
their substrate specificity. Of note, RND-type efflux pump-mediated resistance is of
particular concern with respect to AMR among Gram-negative bacteria. For example,
the chromosomally encoded MexAB-OprM efflux system in P. aeruginosa exhibits broad
substrate specificity and when overexpressed confers fluoroquinolone, aminoglycoside,
and ␤-lactam resistance. Likewise, the overproduction of AcrAB-TolC is characteristic of
multidrug-resistant K. pneumoniae and Enterobacter strains. The A. baumannii AdeABC,
AdeFGH, and AdeIJK RND-type efflux pumps are also associated with broad-range AMR
(234, 238–240). More recently, the chromosomally encoded OqxAB efflux pump, which
contributes to reduced quinolone and chloramphenicol susceptibility, has been iden-
tified in K. pneumoniae (195, 241). OqxAB homologues have also been observed in
some Enterobacter spp., though, aside from tigecycline (242), these elements are not
thought to contribute to clinically relevant drug resistance under in vitro conditions
(241).
Other Mechanisms and Survival Strategies

Biofilms. In addition to the aforementioned classical AMR mechanisms, it is now also
recognized that growth within biofilms can further impede antimicrobial activity.
Biofilms are structured, surface-attached microbial communities encased in an extra-
cellular matrix (ECM) which demonstrate a markedly higher tolerance to antimicrobial
agents than nonadherent planktonic cells (118, 243, 244). Most notably, biofilms play a
prominent role in chronic infections, such as those involving P. aeruginosa in the
airways of patients with cystic fibrosis and indwelling medical device infections caused
by S. aureus and A. baumannii (118, 245). The reduced antibiotic susceptibility exhibited
by biofilm-embedded cells is thought to be multifactorial and can vary according to the
species and genetic makeup of the organism(s), the nature of the antimicrobial agent,
the developmental stage of the biofilm, and the environmental conditions (118, 246).
More recently, it has been recognized that bacterial aggregation can also give rise to
reduced antibiotic susceptibility independent of growth on a surface. Some of the
factors attributable to the increased antibiotic recalcitrance of biofilms include (i)
restriction of antibiotic penetration by the ECM, (ii) the secretion of antibiotic-modifying
enzymes, extracellular DNA, and other macromolecules into the ECM, (iii) the accumu-
lation of filamentous bacteriophages which promote the formation of liquid crystalline
structures, (iv) differential metabolic activity, (v) the emergence of persister cells (see
below), (vi) biofilm-associated upregulation of bacterial efflux, (vii) enhanced horizontal
gene transfer and mutation frequency, and (viii) interactions between different bacte-
rial species within mixed-species biofilms (246–249). A classic example of the last two
factors was reported by Weigel and colleagues, who observed that a plasmid carrying
a vanA vancomycin resistance gene in a VRSA strain arose from a VRE strain present
within the same multispecies biofilm (250).
Antibiotic tolerance and persistence. Aside from antibiotic resistance, which is
characterized by the presence of inheritable resistance-encoding genes or mutations
that give rise to an increased MIC, there is increasing evidence that some ESKAPE
pathogens are able to overcome treatment through antibiotic tolerance. Antibiotic
tolerance enables an entire bacterial population to withstand transient exposures to
high doses of bactericidal antibiotics (e.g., ␤-lactams and quinolones) without a change
in the MIC. This occurs in the absence of any genetic resistance factor and is typically
associated with an arrested (or dormant) growth state which is reversed upon removal
of the antibiotic exposure (251, 252). Antibiotic tolerance can arise from genetic
mutations but may also be conferred by stressful external conditions, including nutrient
limitation, host factors, temperature, and antibiotic treatment (251). Concerningly,
recent studies of MRSA infections in humans also indicate that the evolution of
antibiotic tolerance can facilitate the emergence of mutational resistance (253). Quan-
titative assessment of antibiotic tolerance can be reliably achieved by the minimum
duration for killing of 99% of a bacterial population (MDK99), which evaluates the time

that it takes to eradicate 99% of a bacterial population at antibiotic concentrations that

substantially exceed the MIC (252, 254). In a related phenomenon, antibiotic tolerance
can also be observed among subpopulations of bacterial cells termed “persisters.”
Antibiotic persistence is frequently associated with biofilm infections and is character-
ized by a biphasic MDK99.99 killing curve which displays the emergence of a clonal
persister subpopulation over time. Persister bacterial cells do not respond to antibiotics,
and although they fail to divide in the presence of bactericidal antimicrobials, they are
not killed. Upon treatment cessation, these persistent subpopulations are then able to
resume growth, thus contributing to relapsing or chronic infection (252, 255, 256).
Intracellular survival. Another possible factor contributing to AMR among ESKAPE
pathogens is the observation that some species can be internalized and then survive for
extended periods within host cells. Indeed, recent in vitro studies show that upon
engulfment by alveolar macrophages, both K. pneumoniae and E. faecalis are able to
survive and persist within unique intracellular vacuolar compartments (257, 258).
Likewise, there is accumulating evidence that S. aureus has the capacity to adhere to,
enter, and survive within both professional and nonprofessional phagocytes, including
macrophages; epithelial, endothelial, and mammary cells; keratinocytes; osteoblasts;
and fibroblasts (259, 260). In such instances, it is thus plausible that the microbes are
able to not only evade many of the hosts’ immune defenses but also remain insulated
from the activity of cell-impermeant antibiotics, thus providing a reservoir for dissem-
inated and/or latent infection. Such a scenario was recently illustrated by Lehar and
colleagues, who showed that, compared to extracellular planktonic bacteria, intracel-
lular MRSA isolates exhibit a 100-fold increase in the vancomycin MIC, as well as an
enhanced propensity for systemic dissemination in an antibiotic-treated mouse infec-
tion model (261).
MOBILE GENETIC ELEMENTS CONFERRING ANTIMICROBIAL RESISTANCE

While bacteria can be intrinsically resistant to certain antibiotics, they may also
accumulate AMR genes on MGEs. MGEs are segments of DNA that are capable of
capturing genes and mediating their movement within the genome (intracellular
mobility) or between different cells (intercellular mobility). In this fashion, MGEs are
responsible for much of the observed phenotypic variability in AMR both within and
between bacterial species. The association of AMR and MGEs has been extensively
reviewed recently (262). Thus, here we summarize those elements most relevant to the
ESKAPE pathogens, mainly, plasmids, insertion sequences (IS) and transposons (Tn),
integrative and conjugative elements (ICE), and other genomic islands (GI) (Table 2).
Insertion Sequences and Transposons

IS are small elements (typically, ⬍3 kb) that are capable of self-transposition. The
canonical IS unit is composed of one or two genes required for mobility, flanked by
terminal inverted repeats (IRs) (263, 264). IS are capable of mobilizing neighboring
genes (cargo genes) in structures called composite/compound transposons, where two
copies of an identical or related IS mobilize the region between them (265, 266). Classic
examples of composite transposons associated with the carriage of AMR genes include
Tn9 (IS1; chloramphenicol resistance), Tn10 (IS10; tetracycline resistance), Tn5 (IS50;
aminoglycoside and bleomycin resistance) (262, 265), and, more recently, Tn6330
(ISApl1), which is responsible for mobilizing the colistin resistance gene mcr-1 (135, 262,
267). More complex unit transposons can also be found in both Gram-negative and
Gram-positive bacteria. Unit transposons are large IS-like elements flanked by terminal
IRs with genes (for example, tnpA [transposase] and tnpR [resolvase] in Tn3) that
facilitate replicative transposition. In the ESKAPE pathogens, AMR genes are frequently
associated with the Tn3 family (Tn1, Tn2, and Tn3) (207, 268, 269), Tn7-like unit
transposons (270, 271), and Tn552-like elements (272) (Table 2).
In some cases, single IS elements can also mobilize neighboring genes. ISEcp1 is
commonly associated with the ␤-lactamase genes blaCTX-M (e.g., blaCTX-M-1, blaCTX-M-9,
blaCTX-M-15), blaCMY-2, and blaACC and, more recently, with the blaOXA-181 carbapen-

TABLE 2 MGEs associated with carriage of antimicrobial resistance genes in ESKAPE pathogensa
Species Resistance(s) MGE type MGE Key characteristics Reference(s)
Vancomycin-resistant Vancomycin Tn Tn1546 A composite transposon (IS16) responsible for dissemination of 560, 561
Enterococcus vancomycin resistance in both enterococci and staphylococci
Vancomycin ICE Tn1549-like vanB is typically associated with Tn1549-like and Tn5382-like 334, 335
transposons, which are closely related; significant role in the
global spread of vancomycin resistance
Chloramphenicol, aminoglycosides, tetracycline, Plasmid Inc18-type (e.g., pR23 and pEF-01), Conjugative; broad host range, allowing for transfer into a variety of 262, 562, 563,
kanamycin, MLS, chloramphenicol, RepA_N plasmids (e.g., pRUM-like) bacterial species; responsible for introducing vancomycin 564, 565
streptomycin, vancomycin resistance into MRSA
Methicillin-resistant S. aureus ␤-Lactams Tn Tn552-like elements Tn552 is a complex unit transposon responsible for mobilization and 272
dissemination of ␤-lactam resistance in staphylococci; associated
with a pSK1-like and pSK41-like plasmid

Vancomycin Tn Tn1546 A composite transposon (IS16) responsible for dissemination of
vancomycin resistance in both enterococci and staphylococci
Tetracycline, chloramphenicol, erythromycin Plasmid Small (1- to 10-kb) multicopy plasmids Typically carries a single resistance gene 314–316
␤-Lactams, aminoglycosides, trimethoprim, Plasmid pSK1-like plasmids Associated with carriage of the Tn552-like ␤-lactam resistance 317
antiseptics transposons
Antimicrobial Resistance Profiles of ESKAPE Pathogens
Aminoglycosides, ␤-lactams, vancomycin Plasmid pSK41-like plasmids (e.g., pSK41, Conjugative; associated with carriage of the Tn552-like ␤-lactam 318–321
pGO1, and pLW103) resistance transposons; associated with carriage of vanA on the
Tn1546 glycopeptide resistance transposon
Methicillin, penicillin, ␤-lactams GI SCCmec element SCCmec has a limited distribution and is restricted to 11 major 336–338
clonal lineages of S. aureus from 5 clonal complexes
Methicillin, glycopeptides IS IS1182, IS256 Insertional deactivation, resulting in increased resistance 566, 567
Enterobacterales (K. pneumoniae Multidrug: ␤-lactams, carbapenems, IS ISEcp1, ISCR Typically encodes a promiscuous transposase which can mobilize 273–276, 280,
and Enterobacter spp.) trimethoprim, chloramphenicol, adjacent genes when they fail to identify terminal repeat 568, 569
fluoroquinolones sequences; ISEcp1 elements are commonly associated with
mobilization of ␤-lactamase genes; ISCR elements are commonly
associated with complex class 1 integrons
Carbapenems, colistin IS Various IS, including ISEcp1 Insertional deactivation resulting in increased resistance 276, 281, 282,
570
Multidrug: ␤-lactams, aminoglycosides, Plasmid IncF-type, IncI, IncH (HiI1 and HI2), Typically, low-copy-number plasmids; broad and narrow host 293, 294, 571
trimethoprim, antiseptics, carbapenems, IncL, IncC, IncN, IncH, IncX3 ranges; can act as vehicles for carriage of other mobile resistance
colistin, cephalosporins elements, e.g., transposons and integrons
A. baumannii Multidrug: ␤-lactams, aminoglycosides Tn AbaR, AbGR11 Tn7-like unit transposons 270, 271
chloramphenicol, tetracycline, sulfonamide
Carbapenems Tn Tn2006 The Tn2006 composite transposon (ISAb1) is responsible for
mobilization of the blaOXA-23 carbapenemase
Carbapenems IS ISAb825, ISAb125 Insertional deactivation of the outer membrane protein carO results 223
in elevated carbapenem MICs
Carbapenems IS ISAba1 IS insertion upstream of blaOXA-53 drives expression of the gene; 283
IS-mediated constitutive expression of blaOXA-53 confers high-
level carbapenem resistance
Gentamicin, tobramycin Plasmid pRAY-like plasmids Small (6- to 10-kb), widely distributed plasmids 303, 304
Multidrug: carbapenems and kanamycin Plasmid RepAci6-like plasmids (e.g., pAB-G7-2 Kanamycin resistance is associated with carriage of the TnaphA6 302, 305, 306
and pACICU2), pNDM-BJ01-like transposon; carbapenem resistance is associated with carriage of
plasmids the Tn2006 transposon; pNDM-BJ01-like plasmids from A. lwoffii
carry the blaNDM-1 carbapenemase genes
P. aeruginosa Carbapenems, ␤-lactams IS IS21, ISPA26 Insertional deactivation, resulting in increased resistance 572, 573
Carbapenems Plasmid IncP-2 plasmids Carbapenemases associated with class 1 integrons carried on 309–311
IncP-2-type plasmids
Carbapenems, aminoglycosides ICE P. aeruginosa pathogenicity island Multidrug resistance is associated with carriage of antimicrobial resistance 333
(e.g., PAPI-1, PAGI-2/PAGI-3-like) genes on Tn6162 and Tn6163 elements in a genomic island
aAbbreviations:MGEs, mobile genetic elements; ICE, integrative and conjugative elements; Tn, transposon; IS, insertion sequence; GI, genomic island; MLS, macrolide lincosamide sulfonamides; SCCmec, staphylococcal
cassette chromosome mec.
cmr.asm.org 17
emase gene (273–276). ISEcp1 elements encode promiscuous transposases that can
recognize a variety of different sequences as right IRs (IRr), thereby allowing them to
capture adjacent genes. Related IS (IS1247, ISKpn23, and ISEnca1) have also been
associated with the mobilization of adjacent resistance genes in a manner similar to
that for ISEcp1 (277, 278). Recently, it has been demonstrated that IS26 can produce a
circular intermediate consisting of a single copy of IS26 and a DNA segment immedi-
ately adjacent to it. This structure, termed a translocatable unit (TU), can then move by
a replicative mechanism (279). ISCR elements also form circular intermediates. They
move and can capture adjacent genes by rolling-circle replication (280).
IS elements can also impact the evolution of AMR in the host by the transpositional
deactivation of genes and by modulating the expression of adjacent genes through the
delivery of promoter or terminator sequences (reviewed in reference 264). The inser-
tional deactivation of uptake systems is a common mechanism by which IS elements
can affect antibiotic susceptibilities. For example, IS-mediated deactivation of the
ompK36 porin in K. pneumoniae results in elevated carbapenem MICs (281). Similarly,
insertional inactivation of the mgrB regulatory gene in K. pneumoniae drives the
overexpression of the pmrHFIJKLM operon, conferring colistin resistance (276, 282).
Many IS carry strong promoter sequences, and their insertion upstream of chromo-
somal genes can drive the expression of that gene and influence AMR. This mechanism
is clearly evident in A. baumannii, where insertion of an ISAba1 element upstream of the
blaOXA-51 gene confers carbapenem resistance (283). Similar mechanisms of IS-
mediated constitutive expression of resistance genes have been observed in K. pneu-
moniae and P. aeruginosa (284, 285). Alternatively, an IS may provide only the ⫺35
region promoter component, which, together with a ⫺10 region donated by an
adjacent gene, forms a hybrid promoter to drive the expression of neighboring genes.
Hybrid IS promoters have been identified in at least 17 different bacterial species (286),
including A. baumannii, K. pneumoniae, and P. aeruginosa (283, 287, 288).
Plasmids
Plasmids are an important vehicle for gene transfer in both Gram-negative and
Gram-positive bacteria (289). Typically, plasmids are circular, double-stranded, and
self-replicating DNA molecules that are readily vertically inherited in a growing popu-
lation (290). While it is clear that the MGEs described thus far (IS elements, transposons,
etc.) are primarily responsible for mobilizing resistance genes, the dissemination of
these genes is mainly attributed to conjugative plasmids. Plasmids are rich in IS and
other MGEs carrying AMR genes and facilitate the intra- and interspecies horizontal
transfer of these elements (135, 291–293).
MDR Enterobacterales (K. pneumoniae and Enterobacter species) carry plasmids from
a wide variety of different incompatibility (Inc) groups (294) (Table 2), but those from
Inc group types F (multiple F-type replicons can be found together in multireplicon
plasmids), I, H (HI1 and HI2), L, C, and N are most frequently associated with multidrug
resistance (293, 294). Of particular concern among the Enterobacterales is the role that
these plasmids continue to play in the emergence and dissemination of ESBLs, partic-
ularly those of the blaCTX-M type (19, 295, 296); AmpC-type cephalosporinases (blaCMY-2
and blaDHA-1) (297–299); carbapenemase-encoding genes (blaVIM, blaKPC, blaNDM, and
blaOXA-48) (161, 300, 301); and plasmid-mediated colistin resistance (mcr) (229). Com-
paratively little is known about plasmids from A. baumannii compared to what is known
about plasmids from the Enterobacterales. However, in 2011, a Europe-wide study of
clinical A. baumannii isolates found that resistance plasmids were mainly associated
with carriage of the blaOXA (blaOXA-23, blaOXA-58-like, and blaOXA-40) carbapenemase
genes (302), kanamycin and amikacin resistance, and gentamicin and tobramycin
resistance (303–306). Additionally, plasmids related to pNDM-BJ01 from Acinetobacter
lwoffii carry the globally distributed blaNDM-1 carbapenemase gene (307).
In P. aeruginosa, resistance genes are typically found on chromosomal resistance
islands rather than plasmids. However, P. aeruginosa may carry large (⬃300- to 500-kb),
transferable IncP-2 plasmids (308) associated with the carriage of carbapenemase

genes, specifically, blaIMP (blaIMP-9 and blaIMP-45) (309, 310) and blaVIM (blaVIM-2) (311)
carbapenemases, on class 1 integrons.
AMR plasmids are frequently found in clinical staphylococcal isolates (312, 313).
These include small (1- to 10-kb) multicopy plasmids typically encoding a single
resistance gene (314–316) and larger (⬎15-kb) multiresistance plasmids, such as the
prototype pSK1 family of multiresistance plasmids (317) (Table 2). A single family of
larger (⬎30-kb) conjugative multiresistance plasmids, including pSK41, pGO1, and
pLW1043 (318, 319), can also be found in clinical strains of staphylococci and are
credited with the emergence of aminoglycoside, ␤-lactam, and vancomycin resistance
in S. aureus populations (267, 320–326).
In the enterococci, AMR is largely encoded on Inc18 and RepA_N plasmids (262).
Both Inc18 and RepA_N plasmids have a broad host range, allowing for their transfer
into a variety of bacterial species, and are responsible for introducing vancomycin
resistance into MRSA (218).
Genomic Islands and Integrative Conjugative Elements

Genomic islands (GIs) are discrete genomic loci that have been acquired through
horizontal gene transfer (HGT) (327). Many different types of GIs exist (328–330), and
describing them all is beyond the scope of this review. Here, we only briefly describe
the integrative conjugative elements (ICE) and the SCCmec element.
ICE are conjugative elements that integrate into the host chromosome and that are
passively replicated along with the host genome during cell division (331, 332). In P.
aeruginosa ICE, specifically, the P. aeruginosa pathogenicity/genomic island-type ICE
(PAPI-1, PAGI-2/PAGI-3-like), are the most important for acquired AMR genes (333)
(Table 2). ICE are also important carriers of AMR genes in enterococci (334). Of particular
note is the vanB-associated Tn1549, which has played a significant role in the global
spread of vancomycin resistance (335).
In staphylococci, SCCmec is a genomic island carried in the chromosome of MRSA
isolates (336). The SCCmec element carries the mecA gene, encoding a low-affinity
penicillin-binding protein, PBP2a, that confers resistance to methicillin, penicillin, and
other ␤-lactam antibiotics. Horizontal transfer of the SCCmec element facilitates the
movement of the mecA gene and methicillin resistance among the staphylococci.
However, despite this capacity for mobility, SCCmec has a limited distribution and
appears to be restricted to 11 major clonal lineages of S. aureus from 5 clonal
complexes (337, 338).
Contribution of Horizontal Gene Transfer to the Spread of Mobile Genetic Ele-

ments
HGT facilitates the movement of MGEs between bacteria and is considered the
primary mechanism for the emergence and spread of AMR among pathogenic bacteria
(339). Of the three primary mechanisms of HGT, conjugation, transduction, and trans-
formation, the dissemination of MGEs that carry AMR genes is mostly by conjugation.
Conjugative plasmids and ICE facilitate the rapid dissemination of AMR genes among
bacteria of diverse origins (19, 340–343). Additionally, conjugative plasmids can also
mobilize nonconjugative plasmids, including those with broad host ranges (344).
Although it has been less well studied, there is currently indirect evidence that
transduction can contribute to the spread of AMR genes between members of the
same bacterial species. Bacteriophages isolated from hospital-acquired MRSA, Pseu-
domonas, and Acinetobacter strains have been shown to transduce AMR genes to
recipient strains under laboratory conditions (345–348). There is currently no substan-
tial direct evidence to suggest that transformation contributes to the spread of AMR
among the ESKAPE pathogens. However, Acinetobacter, Pseudomonas, and Staphylo-
coccus strains are all capable of DNA uptake and natural transformation (349). and the
Enterobacterales are predicted to be naturally competent (350, 351). Additionally,
natural transformation can facilitate the transfer of transposons and integrons between

bacterial species (352). Consequently, the potential role that transformation plays in the
spread of AMR genes cannot be overlooked.
Coselection of Antimicrobial Resistance with Detergents and Biocides

Due to the fitness cost imposed by plasmid carriage, plasmids tend to be lost from
bacterial populations under conditions in which they provide no selective advantage
(353, 354). However, antibiotic stewardship programs and the restricted use of key
antibiotics have not been successful in controlling the emergence and spread of AMR.
One mechanism which promotes the persistence of AMR genes in bacterial populations
is coselection with genes that confer resistance to metals and antimicrobial biocides
(355–358). Coselection can result when antibiotic resistance and biocide resistance
share a mechanism, for example, modification of the cell wall/membrane preventing
entry into the cell or upregulation of efflux pumps to remove unwanted compounds
from the cell (359–361). Coselection can also occur when the bacteria carry genes that
promote resistance or decreased susceptibility to both types of antimicrobial com-
pounds. The colocation of AMR and biocide resistance genes on plasmids and other
MGEs (296–298) is particularly problematic, as exposure to the latter can facilitate the
spread of AMR genes by HGT. In 2015, a large-scale study on coselection potential that
examined 2,522 bacterial genomes and 4,582 plasmids found that among plasmids
carrying genes for AMR and biocide resistance, 57% were conjugative, whereas only
18% of plasmids carrying either AMR or biocide resistance genes were conjugative
(357).
Although many different mechanisms of coselection exist, of particular concern in
clinical environments is the qac family of biocide resistance genes, specifically, qacEΔ1,
a truncated version of the qacE gene associated with low-level resistance to quaternary
ammonium compounds (QACs) and other biocides (e.g., biguanides, diamidines, and
xanthenes) (362, 363). qacEΔ1 is frequently found as a component of AMR gene
cassettes on class 1 integrons, which are more prevalent in bacteria exposed to
detergent and other biocides than in bacteria not exposed to these compounds (362,
364, 365). Biocides, such as quaternary ammonium compounds, are heavily used as
cleaning agents in hospitals. Consequently, intertwined AMR and QAC resistance
mechanisms can represent a long-term selection pressure for the maintenance and
spread of AMR in clinical environments (366–369).
Antibiotic stewardship programs are designed to limit the use of key antibiotics to
prevent the spread of AMR. However, in order for these programs to be successful, it
is also important to consider measures which prevent the accumulation of biocides and
other antimicrobial toxicants that can promote coselection.
THERAPEUTIC ADVANCES AGAINST ESKAPE PATHOGENS

Antimicrobial drug discovery is highly challenging, and the current rise in AMR is
eroding the efficacy of available antibiotics (370). Since the early 1960s, only 4 new
classes of antibiotics have been introduced: quinolones, lincosamides, oxazolidinones,
and cyclic lipopeptides. The global financial antibiotic market, estimated at $30 billion,
is still dominated by classes of antibiotics discovered over half a century ago (371).
Frequently, “novel antibiotics” is a term often used for successive compounds derived
from established antibiotic classes (371). The reserved use of such novel drugs as
last-resort measures has constrained the profit margins of the pharmaceutical industry,
leading organizations to withdraw their research effort from antimicrobial drug discov-
ery (370). Economic barriers surrounding the R&D of antimicrobial drug design are
largely instigated by the large operational cost of clinical trials, estimated to be
upwards of $130 million, with postapproval follow-on trials amounting to an added
$146 million (372). Antimicrobial drug candidates targeting more than one clinical
indication require significantly more financial support, further exacerbating the finan-
cial hurdle (373). The financial justification for the development and commercialization
of new therapies often fails to outweigh the value to public health and foregoing
investment (374). Limited by stewardship practices, the net value of an R&D project has

been estimated to be €31.5 million, which in turn considerably weakens the economic
incentive (375). Today, the majority of pharmaceutical companies which do undertake
R&D have few antimicrobial products on the market aimed at the WHO’s priority
pathogen list (376). Due to the absence of revenue from sales, these companies are
largely dependent on external partnering funding sources, such as the U.S. Biomedical
Advanced Research and Development Authority (BARDA), Combating Antibiotic Resis-
tant Bacteria Biopharmaceutical Accelerator (CARB-X), the Wellcome Trust, the National
Institute of Allergy and Infectious Diseases (NIAID), and the Innovative Medicines
Initiative (IMI; a joint undertaking between the European Union and the European
Pharmaceutical Industry), initiatives funded solely and/or in partnership (376–379).
Identifying antibiotic-related health priorities, defining appropriate stewardship prac-
tices, and developing new sustainable economic models to stimulate antibiotic inno-
vation are key intersecting themes currently requiring a cooperative restructure.
Funded by IMI, Driving Reinvestment in Research and Development and Responsible
Antibiotic Use (DRIVE-AB) is a pioneering project composed of 15 public and 7 private
partners from 12 countries aiming to tackle this issue (380). Through the use of
surveillance systems data, antibiotic prescription databases, and published literature,
DRIVE-AB aims to develop models which transform the way in which policy makers
stimulate and financially incentivize antibiotic innovation (380, 381). Despite collabor-
ative projects like these, the majority of new R&D programs aimed at tackling AMR are
currently funded by public and nonprofit partnerships (374). This approach often
neglects obstacles, such as licensing, affordability, and stewardship, which affect access
to new antimicrobials in low- and middle-income countries. Even though antibiotic
drug discovery has reduced and investment from the pharmaceutical industry has
receded, promising antimicrobial strategies are still being developed (Table 3) (371,
382–389).
Recently Approved Drugs

In 2018, three new antibiotics with the potential to treat serious bacterial infections
successfully emerged through clinical trials with either U.S. FDA or E.U. EMA approval
(390) (Table 3). All three drug compounds target the 30S subunit of the bacterial
ribosome. The aminoglycoside class analog plazomicin (Zemdri; Achaogen Inc.) was
approved by the U.S. FDA in June 2018 for the treatment of patients 18 years of age or
older for complicated UTI including pyelonephritis. Plazomicin was not approved by the
U.S. FDA for the treatment of bloodstream infections due to a lack of effectiveness
(390–392). From a randomized trial involving 609 patients, once-daily treatment with
plazomicin was shown to be noninferior to treatment with meropenem (treatment
every 8 h) for use against complicated UTIs and acute pyelonephritis caused by
Enterobacterales, including MDR strains (393). Plazomicin also demonstrated efficacy
better than that of meropenem for eradication of aminoglycoside-resistant and ESBL-
producing Enterobacterales (393).
Eravacycline (Xerava; Tetraphase Pharmaceuticals Inc.) is a tetracycline analog ap-
proved by the U.S. FDA in August 2018 and the E.U. EMA in September 2018 (22, 390,
394) (Table 3). Eravacycline has been developed solely for the treatment of complicated
intra-abdominal infections caused by Gram-negative and Gram-positive ESKAPE patho-
gens, including CRE and CRAB (394). In the IGNITE4 clinical trial, eravacycline was shown
to be noninferior to meropenem for the treatment of complicated intra-abdominal
infections caused by ESBL-producing Enterobacterales (395). Furthermore, patients
treated with eravacycline experienced relatively low rates (3 to 5%) of adverse events,
such as nausea, vomiting, and diarrhea (395).
Omadacycline (Nuzyra; Paratek Pharmaceuticals Inc.), a tetracycline-class drug active
against Gram-negative and Gram-positive ESKAPE pathogens, was approved by the U.S.
FDA in October 2018 for the treatment of CA bacterial pneumonia, acute bacterial skin
and skin structure infection (ABSSSI), and complicated and uncomplicated UTI (390,
396) (Table 3). In a recent clinical trial, once-daily administration through interchanging
intravenous and oral administration demonstrated that omadacycline was noninferior

TABLE 3 Antimicrobial drugs in the clinical pipeline as of February 2020a
Drug name Drug class Drug target Development stage Company Pathogen target Applicationb Information of noteb
Plazomicin (Zemdri) Aminoglycoside 30S subunit of bacterial U.S. FDA approved on 26 June 2018 Achaogen Inc. E. coli, K. pneumoniae, Proteus cUTI including acute Nephrotoxicity has been
ribosome mirabilis, E. cloacae, and CRE pyelonephritis reported
Cefiderocol (Fetroja) Siderophore–␤-lactam PBP U.S. FDA approved on 14 November Shionogi & Co. Ltd. CRE, CRAB, and CRPA cUTI
De Oliveira et al.
(cephalosporin) 2019
Imipenem ⫹ cilastatin ⫹ ␤-Lactam (carbapenem) ⫹ PBP, ␤-lactamase U.S. FDA approved on 17 July 2019; Merck & Co., Inc. CRE and CRPA cUTI including
relebactam (Recarbrio) ␤-lactamase inhibitor E.U. EMA approved on 13 pyelonephritis,
(diazabicyclooctane) February 2020 cIAI, and HA and
VA bacterial
pneumonia
Meropenem- vaborbactam ␤-Lactam (carbapenem) ⫹ PBP, ␤-lactamase U.S. FDA approved on 30 August Rempex Pharmaceuticals E. coli, K. pneumoniae, E. cloacae cUTI including Anaphylactic and central
(Vabomere/Vaborem) ␤-lactamase inhibitor 2017; E.U. EMA approved on 20 Inc. (wholly owned species complex, and CRE pyelonephritis nervous system
(cyclic boronate) November 2018 subsidiary of The reactions have been
Medicines Co.) reported
Cefepime ⫹ zidebactam ␤-Lactam (cephalosporin) ⫹ PBP, ␤-lactamase Phase I Wockhardt Ltd. ESKAPE pathogens, pneumococci, cUTI and HA and VA Highly broad-spectrum

(WCK 5222) ␤-lactamase inhibitor and streptococci bacterial antimicrobial
(diazabicyclooctane) pneumonia
ETX0282 ⫹ cefpodoxime ⫹ ␤-Lactam (cephalosporin) ⫹ PBP, ␤-lactamase Phase I Entasis Therapeutics Inc. MDR A. baumannii and CRAB UTI Designated a QIDP by
proxetil (ETX0282CPDP) ␤-lactamase inhibitor U.S. FDA and
(diazabicyclooctane) awarded fast-track
review
Meropenem ⫹ nacubactam ␤-Lactam (carbapenem) ⫹ PBP, ␤-lactamase, PBP2 Phase I Meiji Seika Pharma Co. CRE, CRPA Bacterial infections
OP0595/RG6080) ␤-lactamase inhibitor Ltd./Fedora
(diazabicyclooctane) Pharmaceuticals Inc.
(Roche licensee)
Cefepime ⫹ AAI101 ␤-Lactam (cephalosporin) ⫹ PBP, ␤-lactamase Phase III Allecra CRE cUTI including Designated a QIDP by
␤-lactamase inhibitor pyelonephritis, U.S. FDA and
(␤-lactam) cIAI, and HA and awarded fast-track
VA bacterial review
pneumonia
Cefepime ⫹ taniborbactam ␤-Lactam (cephalosporin) ⫹ PBP, ␤-lactamase Phase III VenatoRx MDR enteric organisms and ESBL-, cIAI and cUTI Designated a QIDP by
(VNRX-5133) ␤-lactamase inhibitor Pharmaceuticals Inc. KPC-, OXA-, and NDM-, VIM- U.S. FDA and
(cyclic boronate) producing P. aeruginosa awarded fast-track
review
Sulbactam-durlobactam ␤-Lactam (sulbactam) ⫹ PBP, ␤-lactamase Phase III Entasis Therapeutics Inc. CRAB A. baumannii
(ETX2514SUL) ␤-lactamase inhibitor infections
(diazabicyclooctane)
BOS-228 (LYS228) ␤-Lactam (monobactam) PBP Phase II Boston Pharmaceuticals CRE cUTI and cIAI May be used in
(licensed from combination with
Novartis AG) other ␤-lactam
antibiotics
Ceftobiprole (Zeftera) ␤-Lactam (cephalosporin) PBP Phase III; E.U. EMA approved via Basilea Pharmaceutica S. aureus ABSSSI and CA and
decentralized procedure; HA bacterial
Australian TGA approved for HA pneumonia
and CA pneumonia on 8
February 2016; Health Canada
approved for HA and CA
pneumonia on 12 October 2015;
Health Canada approved for
ABSSSI in June 2008
Tebipenem-pivoxil ␤-Lactam (carbapenem) PBP Phase III; Japanese PMDA approved Spero Therapeutics Inc. ESBL-producing E. coli and CA bacterial Oral administration for
(SPR994/SPR859) on 22 April 2009 K. pneumoniae pneumonia and home-based care
complicated UTI
Sulopenem/sulopenem- ␤-Lactam (carbapenem) PBP Phase III Iterum Therapeutics Ltd. MDR Gram-negative pathogens cUTI, uncomplicated Available as oral and
etzadroxil UTI, and cIAI intravenous
preparations
(Continued on next page)
cmr.asm.org 22
TABLE 3 (Continued)
Cefilavancin (TD-1792) Glycopeptide–␤-lactam PG chain elongation, Phase III R-Pharm/Theravance ABSSSI
(cephalosporin) hybrid PBP Biopharma Inc.
Delafloxacin Fluoroquinolone Bacterial type II U.S. FDA approved on 19 June Melinta Therapeutics Inc. ESKAPE pathogens except A. ABSSSI Serious adverse
(Baxdela/Quofenix) topoisomerase 2017; E.U. EMA approved on 16 baumannii reactions, including
December 2019 tendinitis, tendon
rupture, and
neuropathy
Lascufloxacin (Lasvic) Fluoroquinolone Bacterial type II Japanese PMDA approved on 20 Kyorin Pharmaceutical Klebsiella spp, Enterobacter spp., CA bacterial Activity against MRSA
topoisomerase September 2019 Co. Ltd. MRSA, and S. pneumoniae pneumonia comparable to that
of linezolid and
vancomycin
Alalevonadifloxacin ⫹ Fluoroquinolone Bacterial type II Phase III Wockhardt Ltd. MRSA, VRSA, and MDR ABSSSI and HA Active against MSRA
levonadifloxacin (WCK topoisomerase pneumococci, E. coli, and K. bacterial biofilm
771/WCK 2349) pneumoniae pneumonia

OPS-2071 Quinolone Bacterial type II Phase II Otsuka Pharmaceutical C. difficile C. difficile infection
topoisomerase Co. Ltd.
Nemonoxacin (Tiagexyn) Quinolone Bacterial type II Phase II; approved in Taiwan, Russia, TaiGen Biotechnology S. aureus CA bacterial Designated a QIDP by
topoisomerase Turkey, China, and Latin America Co. Ltd. pneumonia, U.S. FDA and
during 2016 diabetic foot awarded fast-track

infection, and review
ABSSSI
Zoliflodacin (ETX0914) Spiropyrimidinetrione Bacterial type II Phase III Entasis Therapeutics Inc. N. gonorrhoeae Uncomplicated N. Designated a QIDP by
topoisomerase gonorrhoeae U.S. FDA and
infection awarded fast-track
review
ACX-362E DNA polymerase IIIC DNA polymerase IIIC Phase 1 Acurx Pharmaceuticals C. difficile C. difficile infections Potential to be applied
inhibitor LLC against all ESKAPE
pathogens
MGB-BP-3 Distamycin DNA minor groove Phase II MGB Biopharma Ltd. C. difficile C. difficile-associated Targets C. difficile in
binder diarrhea vegetative state
before it sporulates
Sodium fusidate (ARV-1801) Fusidane Elongation factor G Phase III; approved (for dosing Arrevus Ltd. MRSA ABSSSI and Granted orphan drug
regimens as an alternative to prosthetic joint designation by U.S.
what is currently being tested in infections FDA
clinical trials) for ABSSSI in South
Korea, Japan, Canada, the
European Union, Australia, New
Zealand, Thailand, India, and
Taiwan
Omadacycline (Nuzyra) Tetracycline 30S subunit of bacterial U.S. FDA approved on 2 October Paratek Pharmaceuticals ESKAPE pathogens CA bacterial Favorable oral and/or
ribosome 2018; E.U. EMA considered Inc. pneumonia and intravenous
granting marketing authorization ABSSSI administration;
Paratek
Pharmaceuticals
withdrew from E.U.
EMA marketing
authorization
approval on 9
October 2019 due to
commercial feasibility
issues
Eravacycline (Xerava) Tetracycline 30S subunit of bacterial U.S. FDA approved on 27 August Tetraphase ESKAPE pathogens, including CRE cIAI Not indicated for
ribosome 2018; E.U. EMA approved on 9 Pharmaceuticals Inc. and CRAB treatment of
September 2018 complicated UTI
KBP-7072 Tetracycline 30S subunit of bacterial Phase I KBP BioSciences CA bacterial Designated a QIDP by
ribosome Pharmaceutical pneumonia U.S. FDA and
Technical Co. Ltd. awarded fast-track
review
cmr.asm.org 23
TABLE 3 (Continued)
TP-271 Tetracycline 30S subunit of bacterial Phase I Tetraphase Respiratory pathogens CA bacterial Designated a QIDP by
ribosome Pharmaceuticals Inc. pneumonia U.S. FDA and
awarded fast-track
De Oliveira et al.
review
TP-6076 Tetracycline 30S subunit of bacterial Phase I Tetraphase CRE and CRAB Bacterial infections CARB-X funded ($4
ribosome Pharmaceuticals Inc. million)
Lefamulin (Xelenta) Pleuromutilin 50S subunit of bacterial U.S. FDA approved on 19 August Nabriva Therapeutics AG MRSA ABSSSI and CA and Low toxicity profile;
ribosome 2019; E.U. EMA marketing HA bacterial available as both
authorization application pneumonia intravenous and oral
submitted in May 2019 (now treatments
accepted); Chinese NMPA
granted clinical trial application
approval on 13 June 2019
Delpazolid (LCB01-0371) Oxazolidinone 50S subunit of bacterial Phase II LegoChem Biosciences Bacterial infections Granted orphan drug

ribosome Inc. and tuberculosis designation, a QIDP,
and fast-track review
by U.S. FDA
DNV3837 (MCB3837) Oxazolidinone-quinolone 50S subunit of bacterial Phase I Deinove SA (formerly C. difficile C. difficile infections Narrow spectrum for C.
hybrid ribosome, bacterial Morphochem AG) difficile, which may
type II reduce gut dysbiosis;
topoisomerase designated a QIDP
by U.S. FDA and
awarded fast-track
review
Contezolid Oxazolidinone 50S subunit of bacterial Phase III MicuRx Pharmaceuticals MRSA and S. pneumoniae ABSSSI
(MRX-I/MRX-415) ribosome Inc.
Nafithromycin (WCK 4873) Macrolide 50S subunit of bacterial Phase II Wockhardt Ltd. MDR pneumococci CA bacterial High level of lung and
ribosome pneumonia alveolar macrophage
penetration; low
hepatic toxicity
SPR206 Polymyxin Cell membrane Phase I Spero Therapeutics Inc. CRE, CRPA, CRAB, and XDR strains cUTI and HA and VA Reduced nephrotoxicity
bacterial
pneumonia
SPR741 Polymyxin Cell membrane Phase I Spero Therapeutics Inc. Gram-negative ESKAPE pathogens Bacterial infections Potentiator with
reduced
nephrotoxicity;
antibiotic paring is
yet to be announced
Afabicin (Debio 1450) Benzofuran naphthyridine FabI Phase II Debiopharm Staphylococcus sp. ABSSI Low propensity for
International SA resistance
development
CG-549 Benzyl pyridinone FabI Phase II Crystal Genomics Inc. MRSA and VRSA ABSSSI
Iclaprim 2,4-Diaminopyrimidine Dihydrofolate reductase Complete response letter to Motif Bio PLC Gram-positive bacteria, including ABSSSI and HA and Granted orphan status
Investigational New Drug MRSA VA bacterial and designated a
application (U.S. FDA) pneumonia QIDP by U.S. FDA;
low propensity for
resistance
development
CRS3123 Diaryldiamine Methionyl-tRNA Phase I Crestone Inc. C. difficile C. difficile infections Narrow spectrum for C.
synthetase difficile, which may
reduce gut dysbiosis
Brilacidin Defensin mimetic Cell membrane Phase II Innovation ABSSSI New class of antibiotic;
Pharmaceuticals Inc. designated a QIDP
by U.S. FDA and
awarded fast-track
review
cmr.asm.org 24
TABLE 3 (Continued)
Murepavadin (POL7080) Antimicrobial peptide LptD Phase III Polyphor Ltd. CRPA HA and VA bacterial Designated a QIDP by
mimetic pneumonia U.S. FDA and

(caused by P. awarded fast-track
aeruginosa) review
Ridinilazole (SMT 19969) Bis-benzimidazole Inhibition of cell Phase III Summit Therapeutics C. difficile C. difficile infection Narrow spectrum for C.
division and PLC difficile, which may
reduction of toxin reduce gut dysbiosis;
production designated a QIDP

by U.S. FDA and
awarded fast-track
review
aThe table includes data from reference 390. Abbreviations: CA, community acquired; HA, hospital acquired; VA, ventilator associated; UTI, urinary tract infection; cUTI, complicated UTI; cIAI, complicated intra-abdominal
infection; ABSSSI, acute bacterial skin and skin structure infection; QIDP, qualified infectious disease product; U.S. FDA, U.S. Food and Drug Administration; E.U. EMA, European Union European Medicines Agency;
Australian TGA, Australian Therapeutic Goods Administration; Chinese NMPA, Chinese National Medical Products Administration; Japanese PMDA, Japanese Pharmaceutical and Medical Devices Agency; BARDA, U.S.
Biomedical Advanced Research and Development Authority; PBP, penicillin-binding protein; PG, peptidoglycan; MRSA, methicillin-resistant S. aureus; CRE, carbapenem-resistant Enterobacterales; CRAB, carbapenem-resistant
A. baumannii; CRPA, carbapenem-resistant P. aeruginosa; XDR, extremely drug resistant.
bAs defined by the company website.
cmr.asm.org 25
to the commonly prescribed moxifloxacin for an early clinical response, as defined by

survival, against CA bacterial pneumonia (397). Unlike the U.S. FDA, the E.U. EMA
recommended granting marketing authorization for omadacycline solely for use in
patients with ABSSSI and not in those with CA bacterial pneumonia. As a result, Paratek
Pharmaceuticals Inc. withdrew omadacycline from the E.U. EMA marketing authoriza-
tion application on 9 October 2019, stating that “it would not be commercially feasible
to market Nuzyra just for the treatment of skin and skin structure infections” (398). The
absence of omadacycline in Europe illustrates the current financial and practical
problems facing antimicrobial R&D, i.e., balancing product profitability with appropriate
stewardship practices. To combat these obstacles, DRIVE-AB has proposed a delinking
initiative which provides a financial reward ($1 billion) per innovative antibiotic, allow-
ing revenues for new antibiotics to be partially or fully delinked from the number of
units sold, thus allowing for the revenues to be based upon the value to society (399).
In 2019, five new antimicrobial drug therapies were approved by either the U.S. FDA,
the E.U. EMA, or the Japanese PMDA. Of these five therapies, four drugs, imipenem-
cilastatin-relebactam (Recarbrio; Merck & Co., Inc.), lefamulin (Xelenta; Nabriva Thera-
peutics AG), lascufloxacin (Lasvic; Kyorin Pharmaceutical Co. Ltd.), and cefiderocol
(Fetroja; Shionogi & Co. Ltd.) demonstrated efficacy against ESKAPE pathogens (note
that pretomanid [TB Alliance] was approved for the treatment of MDR tuberculosis)
(390) (Table 3). In July 2019, the three-drug combination imipenem, cilastatin, and
relebactam was approved by the U.S. FDA for the treatment of complicated UTI and
complicated intra-abdominal infection caused by E. coli, E. cloacae, K. pneumoniae, K.
aerogenes, and P. aeruginosa) (400). Furthermore, the E.U. EMA adopted a positive
opinion for imipenem-cilastatin-relebactam, recommending to grant a marketing au-
thorization for the treatment of infections due to aerobic Gram-negative organisms
in adults with limited treatment options (December 2019). Imipenem-cilastatin-
relebactam was subsequently approved by the E.U. EMA in February 2020 (24).
Imipenem-cilastatin-relebactam, comprised of the existing antibiotics imipenem and
cilastatin, contains a novel ␤-lactamase inhibitor, relebactam, a third new ␤-lactamase
inhibitor after avibactam and vaborbactam (401).
Lefamulin (Xelenta; Nabriva Therapeutics AG), developed for the treatment of CA
bacterial pneumonia, was the second therapeutic to be approved by the U.S. FDA in
2019 (August) (402) (Table 3). In the LEAP 2 trial (a phase III, noninferiority trial that
compared oral lefamulin to oral moxifloxacin), lefamulin demonstrated noninferiority to
moxifloxacin in the management of CA bacterial pneumonia. Lefamulin presents a new
oral and intravenous treatment against CA bacterial pneumonia, particularly for pneu-
monia caused by CA-MRSA (403). In May 2019, Nabriva Therapeutics AG submitted a
marketing authorization application (now accepted) to the E.U. EMA for both intrave-
nous and oral formulations of lefamulin for the treatment of CA bacterial pneumonia in
adults 18 years of age and older (404, 405).
Lascufloxacin (Lasvic; Kyorin Pharmaceutical Co. Ltd.), a novel fluoroquinolone
antimicrobial, was approved by the Japanese PMDA on 20 September 2019 for the
treatment of CA bacterial pneumonia caused by a range of bacterial pathogens,
including quinolone-resistant Staphylococcus and Klebsiella spp. (406–408). In a phase II
clinical trial, oral administration of lascufloxacin (75 mg) demonstrated clinical cure
rates of 90%, bacteriological eradication rates of 96%, and an overall incidence of
adverse drug reaction of 11.1% (409). Furthermore, during a double-blind phase III
clinical trial, lascufloxacin demonstrated noninferiority to orally administered quino-
lones in the management of CA bacterial pneumonia and sinusitis (410).
Cefiderocol (Fetroja; Shionogi & Co. Ltd.), approved by the U.S. FDA in November
2019, is a novel siderophore-cephalosporin conjugate approved for the treatment of
patients 18 years of age or older with complicated UTI including kidney infections
caused by susceptible Gram-negative pathogens (i.e., CRE, CRAB, and carbapenem-
resistant P. aeruginosa [CRPA]) (21, 411) (Table 3). In a phase II, double-blind, random-
ized clinical trial, the safety and efficacy of cefiderocol were assessed. The trial found
that 72.6% of the patients who were administered cefiderocol but only 54.6% who

those who received imipenem-cilastatin had resolution of symptoms and eradication of

bacteria at 7 days posttreatment (412).
New Drug Classes in Clinical Trials

The portfolio of compounds currently in clinical trials more often than not consists
of derivatives of chemical classes for which there is already an underlying mechanism
of resistance. Over the past 24 months, all drugs approved by the U.S. FDA, E.U. EMA,
and Japanese PMDA were drug analogs based on established antibiotic classes (390).
Murepavadin is one of the few new class of antibiotics which entered into a phase III
clinical trial (now temporarily suspended) (Table 3). Murepavadin is selective against the
protein transporter LptD, which mediates the transport of LPS to the outer leaflet (413).
As the first in class of the outer membrane protein-targeting peptidomimetic antibi-
otics, murepavadin displays potent activity against carbapenemase-producing and
polymyxin-resistant P. aeruginosa strains (413). Murepavadin was under clinical devel-
opment for the treatment of HA pneumonia and ventilator-associated (VA) pneumonia.
Unfortunately, enrollment in phase III studies for the systemic treatment of nosocomial
pneumonia has now been temporarily suspended due to higher-than-expected levels
of acute kidney injury in participants. Aerosol formulations of murepavadin for the
treatment of nosocomial and chronic P. aeruginosa respiratory infections are still being
actively pursued (414).
Brilacidin (Innovation Pharmaceuticals Inc.), currently undergoing a phase II clinical
trial, is a synthetic new class of defensin mimetic for the treatment of ABSSSI caused by
S. aureus (Table 3). As a late-stage antibiotic drug candidate, brilacidin is being
advanced to the clinic under the Qualified Infectious Disease Product designation by
the U.S. FDA, enabling fast-track review (390).
New Drugs in Clinical Trials—Overcoming Antibiotic Toxicity

The innate toxicity of certain antibiotics, combined with the compromised state of
the infected patient, often shapes clinical dosing regimens. The rates of drug-induced
nephrotoxicity range from 14% to 26% in adults, and nephrotoxicity is the most
common toxicity issue associated with antibiotic prescription (415). The nephrotoxic
effects of last-resort polymyxin-class antibiotics and the widespread level of carbap-
enem resistance in ESKAPE pathogens have severely limited patient treatment options.
In a bid to overcome these problems, two new polymyxin analogs, SPR206 and SPR741
(Spero Therapeutics Inc.), have been developed (390, 416) (Table 3). SPR206 is an
investigational drug candidate in a phase I clinical trial with broad-spectrum antimi-
crobial activity against polymyxin-sensitive, Gram-negative pathogens (including CRE,
CRPA, and CRAB) associated with complicated UTI, HA pneumonia, and VA pneumonia
(416). SPR741, formerly NAB741, is a potentiator molecule that has been successfully
evaluated in a phase I clinical trial, demonstrating potent synergy with azithromycin,
clarithromycin, erythromycin, fusidic acid, mupirocin, retapamulin, rifampin, and teli-
thromycin (417). SPR741 has the potential to treat a broad range of bacterial disease
states, including those caused by CRE, CRPA, and CRAB strains. In contrast to polymyxin
B, SPR206 yields an aromatic ␤-amino acid modification at the fatty acid-AA1 compo-
nent of polymyxin B. SPR741 lacks two cationic diaminobutyryl residues in the linear
portion of the peptide and lacks the 6-methyloctanoyl or 6-methylheptanoyl fatty acid
tail found in polymyxin B (418). These respective structural modifications have signif-
icantly improved the safety and dose-limiting nephrotoxicity issues associated with
polymyxin-class antibiotics.
Alternative Drug Trial Approaches

New drug trial strategies are emerging, focusing on both alleviating the increased
demand for last-resort therapies and minimizing further infection complications by
reducing patient hospital admission lengths. Such new trial strategies include testing
new antibiotic-antibiotic potentiator combinations and reducing hospital-stay periods
beyond the critical point of infection to improve treatment outcomes.

Carbapenems are still considered the most effective therapy for select ESKAPE
pathogen infections, particularly those caused by ESBL-producing Enterobacterales.
Unfortunately, the increased use of carbapenems in clinical settings has created a
selection pressure for the emergence of carbapenem resistance. In an effort to define
carbapenem-sparing alternatives, a recent drug trial (MERINO trial) examined whether
piperacillin-tazobactam combinations could demonstrate efficacy comparable to that
of carbapenems (419). Among patients with E. coli and K. pneumoniae bloodstream
infections, 30-day survival did not improve upon piperacillin-tazobactam treatment
compared to that achieved with meropenem therapy (420). Although results from the
MERINO trial did not support the use of piperacillin-tazobactam as a carbapenem-
sparing treatment, the trial highlighted the need for carbapenem-sparing strategies
and for further study into ␤-lactam–␤-lactamase inhibitor drug combinations.
Reducing the length of hospital stay following the initial stage of infection is
associated with a decreased risk of further complications and better outcomes of the
patient disease state (421, 422). In 2018, with the objective of reducing patient hospital
admission times, the Partial Oral Treatment of Endocarditis (POET) trial evaluated the
efficacy of intravenous antibiotics compared with that of oral antibiotics among stable
patients with infective endocarditis (423). The premise of this study was to allow patient
treatment to take place outside of hospitals, without the requirement for intravenous
catheters. The primary outcome from the POET study showed that oral antibiotics were
noninferior to intravenous antibiotics at preventing adverse events (i.e., all-cause death,
unplanned cardiac surgery, embolic events, or relapse of bacteremia) (423). The impact
of this landmark study may significantly minimize the challenges associated with
parenteral treatment, including logistics, monitoring, and risks of complications asso-
ciated with intravenous catheters (i.e., secondary local and systemic infections).
Combinational Drug Therapy

The protracted R&D of effective, novel antimicrobial drug candidates has contrib-
uted to the failure to combat the resurgence of AMR bacterial infections. Pairing
existing antimicrobials with either other antimicrobials or nonantimicrobial compounds
offers a valuable strategy to address the problem of AMR. This strategy is not new (424,
425), and it is well recognized that antibiotic monotherapy is not universally efficacious
for all bacterial infections. Adjuvants are often administered in combination with
antibiotic therapy, resulting in better patient outcomes. Antibiotic adjuvants can be
divided into two classes: class I adjuvants, which act on the pathogen, and class II
adjuvants, which act on host properties to potentiate antibiotic action (426).
Blocking resistance mechanisms against existing antibiotics. (i) Class I adjuvants.
From the available repertoire of class I adjuvants, ␤-lactamase inhibitors have proven to
be the most successful. Clavulanic acid, isolated from Streptomyces clavuligerus (427),
inactivates Ser ␤-lactamases and has been paired with amoxicillin for over 30 years to
create the drug Augmentin. Recently, several human clinical trials have examined the
efficacy of class A and C ␤-lactamase inhibitors: avibactam, vaborbactam, and relebac-
tam coformulated with ceftazidime and relebactam paired with imipenem against CRKP
(428). In current clinical practice, ␤-lactamase inhibitors do not inhibit the class B,
Zn-dependent MBLs found broadly in Enterobacterales, Pseudomonas, and Acinetobacter
species (429). The fungus-derived aspergillomarasmine A has been shown to be
efficacious against MBL-producing bacteria in in vivo models of infection (430). Asper-
gillomarasmine A functions to rescue the antibiotic activity of meropenem expressing
NDM-1 and VIM MBLs by sequestering Zn2⫹ ions essential for catalytic activity. Other
antibiotic class I adjuvants which have been investigated include 2-aminoimidazole-
based compounds, which disrupt two-component signaling (431); anthracyclines,
which potentiate rifampin and linezolid (432); SPR741, a polymyxin-derived molecule
designed to minimize nephrotoxicity and potentiate rifampin activity (433); and hy-
droxyquinoline analogues, among others, which potentiate the activity of multiple
classes of antibiotics against a range of Gram-positive AMR pathogens (389, 434).

(ii) Class II adjuvants. Enhancement of host defense mechanisms offers an alterna-

tive set of targets for antibiotic adjuvants. Over the past decade, several innate
immune-enhancing peptides developed to treat sepsis (E-5564 [Eisai Pharmaceuticals]
and TAK-242 [Takeda Pharmaceuticals]) have reached phase III clinical trials but failed
to progress (435). Despite these shortcomings, new immune-stimulating therapies are
continuing to be explored, with promising outcomes.
Recent studies have reported on the synthesis of novel immunotherapeutic com-
pounds which successfully mediate the opsonization of E. coli and P. aeruginosa in
human serum (436). This technology utilizes polymyxin B-hapten conjugates to facili-
tate a two-step process whereby the lipid A binding scaffold of polymyxin B decorates
the surface of Gram-negative bacteria with antibody-recruiting haptens. Mortality
arising from serious infection implies failure of the patient’s innate immune response.
To correct and enhance innate immune cell function, pharmacological strategies have
been centered around hypoxia-inducible factor 1 (HIF), the central regulator of the
cellular response to hypoxic stress (437). HIF has been proposed to be a master
regulator of innate immunity (438). HIF functions to both control the recruitment of
neutrophils to the site of infection and increase the functional neutrophil life span by
inhibiting apoptotic pathways. A series of in vivo infection models has demonstrated
that reduced HIF levels diminish neutrophil function and render mice more susceptible
to serious group A Streptococcus and P. aeruginosa infections (439, 440). Conversely,
elevated levels of HIF have demonstrated enhanced control of MRSA skin infection in
mice (441). HIF modulation has the capacity to serve as a complementary therapy to
classical anti-infective strategies, making it a significant target for immune-boosting
therapy.
Alternative Nondrug Therapies

Preclinical and clinical R&D of new antimicrobials encompasses a wide range of drug
discovery pathways: (i) bacteriophage therapy, (ii) drug repurposing, (iii) monoclonal
antibody (MAb) therapy, (iv) vaccine development, and (v) fecal microbiota transplan-
tation (FMT) are some of the many novel approaches currently being investigated to
control the burden of AMR.
Bacteriophage therapy. Bacteriophage therapy was first applied in 1917 as an oral
preparation to treat dysentery (387). As a result of antibiotic discovery, the use of
bacteriophage treatment significantly reduced. Today, bacteriophage therapy again
represents a potentially effective strategy for the control of AMR bacteria. Within the past
5 years, a number of phage preparations have undergone clinical trials. Examples include
bacteriophage preparations for burn wound infections (ClinicalTrials.gov study identifier
NCT02116010) and persistent postoperative respiratory infection (ClinicalTrials.gov
study identifier NCT00945087) (387).
Through the utilization of the CRISPR technology, several companies have engi-
neered bacteriophages which demonstrate in vivo efficacy against AMR bacterial
infections. These distinct therapies, formulated by Locus and Eligo Bioscience, exploit
the Cas3 and Cas9 enzyme systems, respectively, to degrade bacterial DNA, leading to
cellular death. Therapies developed by both companies are expected to enter clinical
trials within the next 12 months (442).
Although bacteriophages are not currently U.S. FDA approved for human use (due
to the uncertainty surrounding the host immune response), the U.S. FDA has commit-
ted to facilitating the testing of phage therapy in clinical trials. In 2019, the U.S. FDA
accepted an Investigational New Drug application by physician scientists at the Uni-
versity of California, San Diego (443, 444). In collaboration with AmpliPhi Biosciences
Corporation, the proposed phase I/II trial will test AB-SA01, an experimental bacterio-
phage combination for the treatment of ventricular assisted devices infected with MDR
S. aureus. The trial will evaluate the safety, tolerability, and efficacy of intravenously
administered AB-SA01 bacteriophage therapy in combination with complementing
antibiotic therapy (444).
Globally, the lack of an appropriate legal and regulatory framework has been a

significant obstacle to the advancement of phage therapy. In 2016, the Belgium

government began implementing a magistral phage therapy framework that centers
on the magistral preparation (compounded prescription drug product in the United
States) of phage medicines tailor-made for the patient, providing for a broader and
more structured application of phages in Belgium (445). For the proposed magistral
phage strategy process, characterized and quality-tested phages are to be transferred
to a hospital pharmacy for possible incorporation in patient-tailored magistral formulas.
It is anticipated that other European Union members will adopt this phage therapy
framework in the near future, hastening the clinical development of safe-for-human-
use phage therapy.
Repurposing existing drugs used for noninfectious disease. Repurposing existing
drugs represents a viable alternative to de novo drug discovery and favorably reduces
the time, cost, and risk associated with drug innovation (446). Drug repurposing has
already been shown to be efficacious against several Gram-positive and Gram-negative
ESKAPE pathogens. Glatiramer acetate (Copaxone), a widely used treatment for multi-
ple sclerosis, displays antibacterial activity against E. coli, A. baumannii, and, notably, P.
aeruginosa clinical strains isolated from cystic fibrosis patients (447). Ebselen, a syn-
thetic anti-inflammatory drug, and the oncology drugs adarotene and floxuridine have
displayed bactericidal activity against MRSA and VRSA strains in vivo (448, 449). Efforts
to repurpose existing drugs as antimicrobial agents or as antibiotic resistance breakers
are continually being pursued both in the academic sector and in the industrial sector
(371, 389, 450). Due to the marginal incentives of the current pharmaceutical R&D
model for antibiotic development and discovery, drug repurposing may present an
efficacious solution to the burden of AMR.
Monoclonal antibody therapy. Largely used as a therapeutic for oncology and
rheumatic indications, MAb therapy presents a viable alternative for the treatment of
AMR bacterial infections. The bacterial specificity of MAb therapy (i.e., it is not targeted
to the host microflora), combined with a low propensity for resistance development, is
a key feature which makes MAb therapy well positioned for the treatment of AMR
bacterial infections (451). To date, only three MAbs have been approved for clinical use
by the U.S. FDA, and none of them has been directed against ESKAPE pathogens. Both
raxibacumab (Human Genome Sciences, Inc.; approved in December 2012) (452) and
obiltoxaximab (Elusys Therapeutics, Inc.; approved in March 2016) are approved for the
treatment of adult and pediatric patients with inhalational anthrax due to Bacillus
anthracis (453), while bezlotoxumab (Merck Sharp & Dohme Corp.; approved in October
2016) is approved for the prevention of recurrent Clostridioides difficile infection in
high-risk patients (454). Although no existing approved MAb therapy targets ESKAPE
pathogens, several MAb therapies have been clinically evaluated for treatment of
infections caused by MDR P. aeruginosa. Three MAbs, panobacumab (Adris Pharma-
ceuticals), KB001 (KaloBios), and MEDI3902 (AstraZeneca Pharmaceutical Company),
have been evaluated in an early clinical trial targeting MDR P. aeruginosa. Pano-
bacumab, currently in phase II clinical trials, is an antilipopolysaccharide IgM antibody
directed against O-polysaccharide and is under investigation for the treatment of
nosocomial pneumonia caused by P. aeruginosa O11 (455, 456). KB001 is a PEGylated
MAb fragment directed against PcrV (a protein subunit of the P. aeruginosa type III
secretion system) which was evaluated for use in mechanically ventilated CF patients
suffering from chronic P. aeruginosa infection (457). KB001 was observed to be well
tolerated in patients, reduced the levels of the sputum inflammatory marker
interleukin-8, and significantly improved patient lung function (458). Able to facil-
itate opsonophagocytosis in vitro, MEDI3902 is a bivalent, bispecific MAb targeting
PcrV and Psl (an exopolysaccharide involved in colonization and tissue adherence)
(459). During a phase I dose-escalation study, subjects administered MEDI3902
demonstrated no serious treatment-related adverse effects, making it appropriate
for use in ventilated intensive care unit (ICU) patients (460). In the ongoing EVADE
phase II clinical trial, the safety and efficacy of MEDI3902 will be assessed for the
prevention of VA pneumonia in adult ICU patients (461).

Vaccine development. Conceptually, bacterium-targeted vaccine therapies provide

a means to decrease the public demand on existing antibiotics, while they also enable
protection for those who are both vaccinated and unvaccinated (herd immunity).
Unfortunately, vaccines are not currently available for infections caused by ESKAPE
pathogens, with many vaccine candidates failing to elicit an immunogenic protective
effect in clinical trials (462–464).
Of the limited ESKAPE pathogen-targeted vaccines which have recently undergone
clinical trials, the S. aureus 4-antigen vaccine (SA4Ag; Pfizer; which has now ceased
enrollment) was one of the few candidates which demonstrated efficacy in the pre-
vention of invasive S. aureus infection in humans (465). SA4Ag consists of capsular
polysaccharide serotypes 5 and 8 conjugated to the nontoxic mutant form of diphthe-
ria toxin (CRM197), a recombinant mutant clumping factor A (ClfA), and a recombinant
manganese transporter C (MntC) (465). In a phase I/II randomized trial, single-dose
vaccination of healthy adults ranging from 65 to 80 years of age with SA4Ag was shown
to be well tolerated and induced rapid high levels of bacterium-killing antibodies and
sustained immune responses at 12 months postvaccination (465). Unfortunately, in
December 2018, the respective clinical trials ceased enrollment due to meeting its
prespecified futility criteria at an interim efficacy assessment. Despite this, a 36-month
postvaccination serological extension study was still undertaken and recently com-
pleted. In this trial of 440 participants, persistent functional immune responses to S.
aureus antigens were observed through a 36-month time period (466).
In the face of the limited number of vaccines in the clinical pipeline, encouraging
preclinical studies have recently demonstrated the in vivo efficacy of vaccines against
CRKP (467), P. aeruginosa (462), and A. baumannii (468). Vaccines have already been
shown to be very effective at reducing the incidence of other AMR pathogens, such as
Streptococcus pneumoniae and Haemophilus influenzae type b (464). The prospect of
new ESKAPE-targeted vaccines which complement existing AMR therapies will signifi-
cantly aid in mitigating the spread and threat of ESKAPE pathogens.
FMT strategies. Antibiotic exposure, particularly in long-term acute care hospital
patients, can alter the patient microbiota and significantly reduce colonization resis-
tance (469). FMT-based approaches are currently being investigated for protection
against AMR bacterial colonization. A recent study demonstrated that blood disorder
patients treated with multiple FMT procedures exhibited gastrointestinal decoloniza-
tion of VRE, ESBL-producing Enterobacterales, CRE, and CRPA in 60% of all cases (470).
These data highlight the utility of FMT approaches in reversing the gut dysbiosis that
predisposes patients to colonization with AMR ESKAPE pathogens.
OUTLOOK
AMR represents one of the few challenges that unites global interests and concerns
for human and animal health and the food and agricultural sectors. Exacerbated by the
acquisition of AMR genes, ESKAPE pathogens represent the paradigm for resistance,
pathogenesis, and disease transmission in both the community and clinical settings.
Although heterogeneous at the genetic level, the general mechanisms surrounding
ESKAPE pathogen emergence and persistence are broadly shared. Mediated in part
through HGT, resistance strategies encompassing drug inactivation, modification of the
antibiotic target site, and a reduction of antibiotic accumulation in the bacterial cell are
common strategies shared by all ESKAPE pathogens. Combined with the collective
ability to form biofilm on innate and biological surfaces, ESKAPE pathogens remain
highly prevalent in clinical settings.
To constrain the spread of ESKAPE pathogens, it is now well recognized that
collaborative global and regional efforts are required by policy makers, funders, and
those responsible for the treatment and management of ESKAPE pathogens (12, 35, 64).
Aside from novel drug development, these collaborative endeavors will require sus-
tainable stewardship practices to reduce the inappropriate use of antibiotics in both the
human health and agricultural sectors. Despite efforts to coordinate international and
national AMR surveillance, it would be well-advised for AMR policy, drug development,

and surveillance efforts to include both ESKAPE pathogens and other serious health
threats, such as AMR E. coli, Neisseria gonorrhoeae, and Campylobacter spp. These will
require equal attention to avoid selecting for a new group of AMR pathogen threats
(12). Improvements in factors encompassing AMR surveillance, diagnostics, patient
education, and patient treatment options will together help facilitate the control
of AMR.
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David M. P. De Oliveira is currently a Re- Timothy J. Kidd completed a B.Appl.Sc. in

search Fellow at the Australian Infectious Dis- microbiology and biotechnology at the
eases Research Centre, University of Queens- Queensland University of Technology in
land. He completed his Ph.D. studies in 1998 and thereafter worked as a senior sci-
December 2015 at the Illawarra Health and entist within various clinical microbiology
Medical Research Institute at the University laboratories located in Queensland, Austra-
of Wollongong. His Ph.D. thesis focused on lia. In 2012, he received his Ph.D. in medical
characterizing novel host-bacterial interac- microbiology at The University of Queens-
tions which contribute to group A strepto- land, Australia. Between 2014 and 2019 he
coccal pathogenesis. His current research secured successive European Respiratory So-
themes center around novel infectious dis- ciety RESPIRE2 Marie Sklodowska-Curie Post-
ease therapies, with a particular focus on repurposing existing nonan- doctoral and National Health and Medical Research Council Early Career
timicrobial therapies into direct-acting or potentiating antimicrobial Fellowships based at Queen’s University of Belfast, United Kingdom,
therapies which target AMR bacterial pathogens. and The University of Queensland. He currently holds a combined
research and teaching position within the School of Chemistry and
Molecular Biosciences at The University of Queensland. His research
Brian M. Forde completed a Ph.D. at Univer- interests focus on cystic fibrosis (CF) airway infections and Klebsiella
sity College Cork, Ireland, in 2012. He joined pneumoniae infection biology, in particular, the epidemiology and
The University of Queensland in 2012 as a transmission of CF pathogens, the mechanisms and detection of anti-
Postdoctoral Fellow at the School of Chemistry microbial resistance, as well as the characterization of novel K. pneu-
and Molecular Biosciences (SCMB). He is cur- moniae virulence determinants.
rently a Research Fellow at the SCMB and The
University of Queensland Centre for Clinical
Research (UQCCR). His research his focused
on the use of whole-genome sequencing for
the surveillance of multidrug-resistant hu-
man pathogens in clinical and public health
microbiology, real-time tracking of transmission routes during nosoco-
mial outbreaks, and the implementation of genomic research into
clinical practice.

Patrick N. A. Harris is an Infectious Disease David L. Paterson is a Director at The Uni-

Physician, Medical Microbiologist, and NHMRC versity of Queensland Centre for Clinical Re-
Early Career Research Fellow at The University search. He is also a Consultant Infectious
of Queensland Centre for Clinical Research Diseases Physician at the Royal Brisbane and
(UQCCR). He completed his Ph.D. in 2018 Women’s Hospital. He received his medical
under the supervision of Prof. David Pater- degree and Ph.D. from The University of
son. He was the lead author on the MERINO Queensland. Dr. Paterson has received re-
trial, reported in JAMA in 2018. His research search funding from the Centers for Disease
has a focus on antibiotic-resistant bacteria Control and Prevention (CDC), Australia’s Na-
and the use of randomized clinical trials to tional Health and Medical and Medical Re-
define the optimal treatment for these prob- search Council (NHMRC), and the Medical
lematic infections as well as the application of bacterial genomics to Research Future Fund. A 2008 Frank Fenner Award for Advanced Re-
clinical practice. search in Infectious Diseases by the Australasian Society for Infectious
Diseases (ASID) quickly followed, and in 2009 he was awarded a
Queensland Health Senior Clinical Research Fellowship and subse-
Mark A. Schembri is an Australian National quently 2 NHMRC Practitioner Fellowships. He is now an NHMRC inves-
Health & Medical Research Council Senior tigator grant holder. His research focuses on the molecular and clinical
Research Fellow and Deputy Director of the epidemiology of infections with AMR organisms, with the intent of
Australian Infectious Diseases Research Cen- translation of knowledge into optimal prevention and treatment of
tre at The University of Queensland. Dr. these infections.
Schembri completed his Ph.D. at Monash
University and postdoctoral studies at the
Technical University of Denmark. In 2001, he Mark J. Walker is the Director of the Austra-
was awarded a Fellowship from the Danish lian Infectious Disease Research Centre, a mul-
Natural Sciences Research Council and ap- tidisciplinary network based at The University
pointed to Lecturer. He joined The University of Queensland, and the QIMR Berghofer Med-
of Queensland in 2004 as a Senior Lecturer and was promoted to ical Research Centre. He was awarded an
Reader in 2007 and to Professor in 2010. Dr. Schembri’s research is in Alexander Von Humboldt Fellowship in 1998
the field of molecular microbiology and bacterial pathogenesis. His and a Fulbright Senior Scholar Fellowship in
specialist interest is in the area of uropathogenic Escherichia coli (UPEC), 2005. Dr. Walker was elected a Fellow of the
with a focus on the genetics, genomics, and virulence of multidrug- American Academy for Microbiology in 2013.
resistant UPEC clones and the role of cell surface factors in UPEC He works with a collaborative network of
adhesion, aggregation, biofilm formation, and colonization of the uri- Australian and international researchers to
nary tract. understand the emergence and evolution of AMR in bacterial patho-
gens, investigate host-pathogen interactions, and translate these re-
search findings into new therapeutics and vaccines.
Scott A. Beatson is a Group Leader at The
University of Queensland (UQ) and a mem-
ber of the Australian Infectious Diseases Re-
search Centre. In 2002 Dr. Beatson was
awarded a Ph.D. from UQ in the area of
bacterial genomics and pathogenesis. He
completed Postdoctoral Fellowships in bioin-
formatics at the University of Oxford and the
University of Birmingham before returning
to UQ as a National Health and Medical Re-
search Fellow (NHMRC) Howard Florey Re-
search Fellow. In 2008, he established the Microbial Genomics Group at
UQ and has since been supported by fellowships from both the Aus-
tralian Research Council and NHMRC. He uses genomics to investigate
transmission, pathogenesis, and antibiotic resistance in bacteria, with a
focus on mobile genetic elements. Recent work includes genomic
investigations of AMR pathogens causing hospital outbreaks and phy-
logenomic analyses of the pandemic multidrug-resistant Escherichia coli
ST131 clone.

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REVIEW

Antimicrobial Resistance in ESKAPE Pathogens

July 2020 Volume 33 Issue 3 e00181-19 Clinical Microbiology Reviews cmr.asm.org 1

SUMMARY Antimicrobial-resistant ESKAPE (Enterococcus faecium, Staphylococcus au-

T he emergence of multidrug-resistant (MDR) bacteria (bacteria resistant to more

July 2020 Volume 33 Issue 3 e00181-19 cmr.asm.org 2

METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS

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nosocomial infections, there is also increasing acknowledgment of P. aeruginosa as a

July 2020 Volume 33 Issue 3 e00181-19 cmr.asm.org 7

ESKAPE PATHOGEN MECHANISMS OF ANTIBIOTIC RESISTANCE

July 2020 Volume 33 Issue 3 e00181-19 cmr.asm.org 8

(e.g., penicillinase) ESKAPE pathogens. Indeed, blaZ-encoded penicillinases that

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Target Site Modiﬁcations

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misidentiﬁed as methicillin-sensitive S. aureus, proving a particular problem in the

July 2020 Volume 33 Issue 3 e00181-19 cmr.asm.org 12

ESKAPE organism resistance to linezolid and aminoglycosides is also mediated at the

July 2020 Volume 33 Issue 3 e00181-19 cmr.asm.org 13

Reduced Antibiotic Penetration and Accumulation

July 2020 Volume 33 Issue 3 e00181-19 cmr.asm.org 14

Other Mechanisms and Survival Strategies

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that it takes to eradicate 99% of a bacterial population at antibiotic concentrations that

MOBILE GENETIC ELEMENTS CONFERRING ANTIMICROBIAL RESISTANCE

Insertion Sequences and Transposons

July 2020 Volume 33 Issue 3 e00181-19 cmr.asm.org 16

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Genomic Islands and Integrative Conjugative Elements

Contribution of Horizontal Gene Transfer to the Spread of Mobile Genetic Ele-

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Coselection of Antimicrobial Resistance with Detergents and Biocides

THERAPEUTIC ADVANCES AGAINST ESKAPE PATHOGENS

July 2020 Volume 33 Issue 3 e00181-19 cmr.asm.org 20

Recently Approved Drugs

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during 2016 diabetic foot awarded fast-track

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production designated a QIDP

to the commonly prescribed moxiﬂoxacin for an early clinical response, as deﬁned by

July 2020 Volume 33 Issue 3 e00181-19 cmr.asm.org 26

those who received imipenem-cilastatin had resolution of symptoms and eradication of

New Drug Classes in Clinical Trials

New Drugs in Clinical Trials—Overcoming Antibiotic Toxicity

Alternative Drug Trial Approaches

July 2020 Volume 33 Issue 3 e00181-19 cmr.asm.org 27

Combinational Drug Therapy

July 2020 Volume 33 Issue 3 e00181-19 cmr.asm.org 28

(ii) Class II adjuvants. Enhancement of host defense mechanisms offers an alterna-

Alternative Nondrug Therapies