Treatment of Bloodstream Infections Due To Gram-Ne

antibiotics
Review
Treatment of Bloodstream Infections Due to
Gram-Negative Bacteria with
Difficult-to-Treat Resistance
Matteo Bassetti 1,2 , Antonio Vena 1, * , Chiara Sepulcri 1 , Daniele Roberto Giacobbe 1 and
Maddalena Peghin 3
1 Clinica Malattie Infettive, Ospedale Policlinico San Martino—IRCCS, 16132 Genoa, Italy;
matteo.bassetti@unige.it (M.B.); chiara.sepulcri@gmail.com (C.S.);
daniele.roberto.giacobbe@gmail.com (D.R.G.)
2 Department of Health Sciences, University of Genoa, 16132 Genoa, Italy
3 Department of Medicine, Infectious Diseases Clinic, University of Udine and Azienda Sanitaria
Universitaria Integrata, 33100 Udine, Italy; maddalena.peghin@gmail.com
* Correspondence: anton.vena@gmail.com; Tel.: +39-010-5554672

Received: 7 July 2020; Accepted: 13 September 2020; Published: 22 September 2020
Abstract: The rising incidence of bloodstream infections (BSI) due to Gram-negative bacteria (GNB)
with difficult-to-treat resistance (DTR) has been recognized as a global emergency. The aim of
this review is to provide a comprehensive assessment of the mechanisms of antibiotic resistance,
epidemiology and treatment options for BSI caused by GNB with DTR, namely extended-spectrum
Beta-lactamase-producing Enterobacteriales; carbapenem-resistant Enterobacteriales; DTR Pseudomonas
aeruginosa; and DTR Acinetobacter baumannii.
Keywords: Gram-negative bacteria; difficult to treat bacteria; Enterobacteriales; Pseudomonas aeruginosa;

Acinetobacter baumannii
1. Introduction
In the last two decades, antibiotic resistance has grown at such a pace, and spread so widely,
that it has been recognized as a global emergency.
Among the pathogens causing concern, Gram-negative bacteria (GNB) have raised the most
attention, due to the rapid increase in their association with morbidity and mortality all over
the world [1]. Bloodstream infections (BSI), present in 40% of cases of community-acquired and
hospital-acquired sepsis and septic shock, are associated with poor outcomes, especially with delayed
adequate antimicrobial therapy and source control [2]. GNB BSI isolates represent an usufeul
surveillance target for the monitoring of resistance, as cultures from sterile sites avoid the problem of
confounding colonizing agents.
In 2008, the US and European Centers for Disease Control and Prevention (CDC and ECDC)
proposed a classification of resistance based on the phenotypic profiles of resistance to antimicrobials.
Three resistance phenotypes were defined: multidrug resistance (MDR), defined as non-susceptibility
to ≥1 agents in ≥3 antimicrobial categories; extensive drug resistance (XDR), susceptibility limited
to ≤2 categories; and pan-drug resistance (PDR), non-susceptibility to all agents in all antimicrobial
categories [3]. This classification has been extensively used in the literature, but its usefulness in
clinical practice has been recently questioned [4]. Despite their advantages for epidemiological studies,
these definitions share several limitations, as they do not differentiate between or prioritize antibiotic
classes according to their efficacy or toxicity and mean that very broad classes of antibiotics must be
tested. Above all, the problem is that their use does not correlate with clinical outcomes [5].
Antibiotics 2020, 9, 632; doi:10.3390/antibiotics9090632 www.mdpi.com/journal/antibiotics

Antibiotics 2020, 9, 632 2 of 18
In 2018, Kadri et al. proposed a new term for the multidrug resistance profile of GNB, namely difficult-
to-treat resistance (DTR), which these authors defined as any GNB-BSI isolates demonstrating
an intermediate or resistant phenotype to all first line agents in the carbapenem, beta-lactam,
and fluoroquinolone categories [5]. DTR means non-susceptibility to all first-line, high-efficacy,
low-toxicity agents and focuses on the effect of resistance on treatment decisions and clinical outcomes.
This new definition has already been accepted by several authors, and its association with clinical
outcomes is currently under evaluation. It has received both praise and criticism, since with the
introduction of new antibiotics, the concept of DTR will evolve in keeping with the assessment of what
constitutes first-line treatment [6–8].
The rising incidence of BSI due to GNB with DTR is a matter of serious concern, both in the
community and in the hospital setting [2,9]. The aim of this review is to provide a comprehensive
assessment of the currently available and emerging treatment options for BSI caused by GNB with DTR,
namely extended-spectrum Beta-lactamase (ESBL)-producing Enterobacteriales; carbapenem-resistant
Enterobacteriales (CRE); DTR Pseudomonas aeruginosa; and DTR Acinetobacter baumannii.
2. DTR Pathogens: Mechanisms of Antibiotic Resistance and Epidemiology
2.1. Enterobacteriales
The bacterial mechanisms most commonly involved in antibiotic resistance are the modification
of the antibiotic molecule, decreased antibiotic penetration and efflux, changes in the antibiotic target
site, and global cell adaptation. DTR Enterobacteriales mechanisms of resistance mainly rely on the
production of beta-lactamases, enzymes that catalyze the destruction of the amine bond of beta-lactam
antibiotics in the periplasmic space. These enzymes have been extensively studied, and are normally
classified using the Ambler classification. The Ambler scheme divides β-lactamases into four major
classes (A to D), according to their amino acid similarity. In the Ambler scheme, β-lactamases of classes
A, C and D are classified as serine β-lactamases (Table 1).
2.2. ESBL-Producing Enterobacteriales

ESBLs are a group of beta-lactamases that confer resistance to penicillins, third generation
cephalosporins (the hallmark characteristic) and monobactams, while they are inactive against
carbapenems. The main ones (TEM-, SHV- and CTX-M-type enzymes) fall under Ambler class A and
are plasmid-encoded, while other enzymes, such as AmpC and Oxa-11, are included in classes C and D
respectively. Since their discovery in the 1960s, their prevalence has been rising worldwide. Although
global data on the prevalence of specific mechanism of resistance are still lacking, the 2018 ECDC
surveillance report showed that the prevalence of E.coli resistant to third generation cephalosporins
in the EU/EEA region was 15.1%, while that of K. pneumoniae reached 31.7%, with peaks of >50% in
Italy, Portugal and Eastern Europe. ESBL-producing Enterobacteriales are frequently encountered as
colonizers or causes of infections, both in the community and in the hospital setting [10].
2.3. Carbapenem-Resistant Enterobacteriales

Resistance to carbapenems is caused by the production of carbapenemases, which fall under more
than one Ambler class. Less frequently, carbapenem resistance stems from deficient outer-membrane
protein expression. In Ambler class A, the main enzymes are KPC (Klebsiella pneumoniae carbapenemase),
which is plasmidic, and SME (Serratia marcescens enzyme), which is chromosomally transmitted;
these enzymes are not inhibited by aztreonam, which they hydrolyze [11] (Table 1).
Table 1. Classification of most frequent extend ed-spectrum β-lactamases and carpapenemase, spectrum of activity, inhibition, relevant organism and
geographic distribution.
Activity Inhibited by
Activity against Activity against Activity against Inhibited by Inhibited by Inhibited by Inhibited by Relevant Geographic
Molecular Class Enzymes against Vaborbactam
Cephalosporins Carbapenems Aztreonam Carbapenems Clavulanic Acid Tazobactam Avibactam Organisms Distribution
Penicillins and Relebactam
Worldwide spread.
ESBL (TEM, E. coli
Yes, except Community and
SHV, CTX-M, Yes No Yes Yes Yes Yes Yes Yes Klebsiella spp.
cefamycins nosocomial
others) P. mirabilis
infections
A (serine
penicillinases) E. coli Worldwide
K. pneumoniae United States
Yes K. oxytoca South and Central
KPC Yes Yes Yes No No No Yes Yes
Strong activity S. marcescens America Europe
Enterobacter spp. (mainly Italy and
C. freundii Greece)
NDM: Asia
(mainly India,
E. coli Pakistan and
K. pneumoniae Bangladesh); Italy
MBLs (VIM,
B Yes K. oxytoca, (Tuscany)
IMP, NDM, Yes Yes No No No No No Yes
(metallo-β-lactamases) Strong activity S. marcescens, IMP and VIM:
others)
Enterobacter spp. Europe (Romania,
C. freundii Poland and
Denmark)
K. pneumoniae
E. coli
AmpC type Yes except Worldwide spread.
No Enterobacter spp.
(CMY-2, cefepime, Community and
C (cephalosporinases) Yes No Yes Yes No High Yes Yes S. enteritidis
DHA-1, FOX-1, including nosocomial
concentrations C. freundii
others) cefamycins infections
S. marcescens
A.baumannii
Relatively
common in
A. baumannii Europe
OXA (OXA-48, Yes
P. aeruginosa (Mediterranean
OXA-23, Weak activity
Yes E.coli countries),
D (oxacillinases) OXA-11, Yes § against Yes No Weak Weak Yes No
Weak activity * K. pneumoniae Northern Africa
OXA-181, cefepime and
P. mirabilis and Middle
others) ceftazidime
C. freundii Eastern countries
Extremely rare in
United States
Abbreviation: ESBL, Extended-spectrum β-lactamases; IMP, Imipenemase Metallo-beta-lactamase; KPC, Klebsiella pneumoniae carbapenemase; MBLs, metallo-β-lactamases; NDM,
New Delhi metallo-betalactamase; OXA-48, oxacillinase-48; OXA-23, oxacillinase-23; VIM, Verona integron-encoded metallo-beta-lactamase. § Except cloxacillin * High-level carbapenem
resistance may occur when these enzymes are found in combination with other β-lactamases (ESBL-od Amp-C), or with membrane permeability alteration.
Enzymes classified in Ambler class B are all carbapenemases belonging to the metallo beta-lactamase
(MBL) group, due to their beta-lactamase activity through a metal ion (usually zinc) as cofactor. There are
three main MBLs: imipenemase (IMP), Verona integron-encoded metallo beta-lactamase (VIM) and
New Delhi metallo beta-lactamase (NDM). Encoded by plasmids or other mobile genetic elements,
these MBLs are spreading rapidly all over the world and are now the mechanism of resistance of
greatest concern; they are frequently associated with the expression of additional genes conferring
resistance to other antimicrobial drug classes such as fluoroquinolones and aminoglycosides, and thus
narrow the spectrum of therapeutic options. They are not inhibited by old beta-lactamases inhibitors
(clavulanic acid or tazobactam) or by new ones (avibactam, relebactam or vaborbactam), but they
remain susceptible to aztreonam [12] (Table 1). The ability of these enzymes to spread rapidly is
demonstrated by their capacity to cause outbreaks in non-endemic regions, as recently occurred in the
outbreak of NDM-producing K. pneumoniae in Tuscany [13,14].
Class D enzymes pertain to the OXA-48 class, and have an unusual mechanism of resistance;
they are penicillinases (particularly oxacillinases) and carbapenamases, but they are susceptible to
third generation cephalosporins, although they frequently co-produce as ESBL enzymes and thus
confer resistance to all beta-lactams [15]. They were first described in a K. pneumoniae isolate in Turkey,
but can be now found in all Enterobacteriales (especially E. coli) throughout the world, particularly in
North Africa and the Middle East, where they are endemic [16].
From the epidemiological point of view, data from the latest ECDC report showed that carbapenem
resistance remained rare (<1%), although several countries reported high percentages (above 10% or
even 25%) of carbapenem-resistant K. pneumoniae, including Italy, France, Spain, Portugal and most
Eastern European countries. Greece reported the highest levels of resistance with a prevalence of
50% [10].
Carbapenem-resistant Enterobacteriales (CRE) enzymes (except for OXA-48) are mainly encountered
in the hospital setting in patients receiving prolonged antibiotic therapy, carrying indwelling devices,
or undergoing long-term hospitalization or ICU admission [17].
2.4. Pseudomonas aeruginosa

P. aeruginosa deploys almost all the resistance mechanisms available to bacteria to protect itself
from the action of antibiotics, and is one of the most difficult organisms to treat. Its preferred
mechanism of resistance involves the efflux pumps that remove beta-lactams and fluoroquinolones,
as well as many dyes and detergents. Other mechanisms include the production of inducible AmpC
enzyme, the loss of impermeability due to loss of porin OprD, which is particularly associated with a
reduced susceptibility to carbapenems, and acquired enzymatic mechanisms of resistance, such as
OXA, ESBL enzymes and MBL enzymes, which have led to the spread of multidrug resistance [18].
In 2018, about 19% of P. aeruginosa isolates in the EU/EEA were resistant to fluoroquinolones, 18.3% to
piperacillin/tazobactam, 17.2% to carbapenems and 14.1% to ceftazidime. Combined resistances to
two, three or five antimicrobial classes were 7.6%, 4.1% and 4.1% respectively—rates that indicate the
need for new drugs active against these DTR strains [10] (Table 1).
2.5. Acinetobacter baumannii Complex

Like P. aeruginosa, species of the A. baumannii complex have developed multiple mechanisms
of resistance to many classes of antibiotics, and have often become DTR organisms in the context
of healthcare-associated infections. The principal mechanisms of resistance are the production
of chromosomally encoded AmpC cephalosporinases (as well as other β-lactamases of the TEM,
CTX-M SHV type). However, the most recent and worrisome mechanism of resistance is the production
of carbapenemases (both serine and MBLs), which, in the case of the A. baumannii complex, are mainly
OXA-23 for the serine type and IMPs and VIMs for the MBL class. Other typical mechanisms of
resistance are changes in the porins, production of aminoglycoside-modifying enzymes, and efflux
pumps [19]. The prevalence of antibiotic resistance among A. baumannii complex isolates is a matter
of particular concern. In 2018, in the EU/EEA, 31.9% of isolates were reported to be resistant to
carbapenems; the same percentage were resistant to aminoglycosides and an even higher percentage
to fluoroquinolones (36.2%); 28.8% of isolates presented combined resistance to all these three classes,
a situation that severely jeopardized treatment options [10] (Table 1).
3. Novel Treatment Options
3.1. Ceftolozane/Tazobactam
Ceftolozane/tazobactam (C/T) is a novel β-lactam/β-lactamase inhibitor (BL/BLI), which exhibits
excellent in vitro activity against Pseudomonas aeruginosa, including drug-resistant strains, and other
Enterobacteriales including most ESBL. This new drug is currently EMA and FDA approved for the
treatment of complicated intra-abdominal infections (cIAI) (in combination with metronidazole) and
complicated urinary tract infections (cUTI) on the strength of the results of the ASPECT-cIAI and
ASPECT-cUTI trials [20,21]. Recently, C/T has also been approved for hospital-acquired pneumonia (HAP)
and ventilator-associated pneumonia (VAP), since high-dose ceftolozane/tazobactam (3 g q 8 h) achieved
non-inferiority vs. meropenem in the ASPECT-nosocomial pneumonia (NP) trial [22] (Tables 2 and 3).
3.2. ESBL
Carbapenems remain the treatment of choice for severe ESBL infections [23]. The role of carbapenem-
sparing regimens for ESBL infections in order to reduce selective antimicrobial pressure is unclear.
The data available on the use of ceftolozane–tazobactam for ESBL pathogens are limited, and are
mainly extrapolated from pivotal clinical trials. Regarding ESBL producers, the activity of C/T has
been shown to be superior overall to that of piperacillin/tazobactam, but meropenem showed better
in vitro activity against Enterobacteriales, especially against ESBL-producing strains. Nonetheless,
when patients with ESBL infections treated with ceftolozane–tazobactam were compared to those
receiving meropenem, there were no differences in terms of clinical outcomes between treatment
groups [22,24,25].
A recent Italian multicenter retrospective study reported the largest clinical experience regarding
the use of C/T therapy for the treatment of serious ESBL-producing Enterobacteriales infections in daily
clinical practice (NP 31.7%, acute bacterial skin and skin-structure infection [SSTI] 20.8%, cUTI 13.9%,
cIAI 12.9%, bone infection 8.9% and primary bacteremia 5.9%), and showed C/T to be a valid option in
empiric and/or targeted therapy, with favorable clinical outcomes in 128/153 (83.7%). Interestingly,
the risk of clinical failure was associated with standard-dose C/T therapy in septic patients receiving
continuous renal replacement therapy (CRRT) [26].
The use of ceftolozane/tazobactam as a carbapenem-sparing strategy for infections due to
ESBL-producing Enterobacteriales has also been proposed, and may be useful and cost-effective in
selected scenarios depending on local antibiotic stewardship decisions [27]. More evidence is needed
to define the therapeutic role of ceftolozane/tazobactam for ESBL infections [28].
AmpC producers are susceptible to C/T to different degrees, depending on the bacterial species
and enzyme types in question. Although there is no relevant clinical information, the activity of
C/T against Enterobacteriales with copious AmpC enzyme is variable, and many Enterobacter spp.
with de-repressed AmpC are resistant to this antibiotic, which should not be used in infections due to
AmpC-producing species [29,30].
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Table 2. Spectrum
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6Novel
Aztreonam-Avibactam
Cefepime/Zidebactam
Novel
Novel CRE-OXA48
ESBLCRE-KPC
CRE-MBL
ESBL
CRE-KPC
6 767
Tetracycline
Tetracycline
Cephalosporine CRE-OXA48
CRE-KPC
CRE-MBL
DTR P.
CRE-OXA48
7 7 88 DTR
CRE-MBL Aeruginosa
CRE-MBL88 CRE-MBL
Acinetobacter
ESBL P.
DTR
6886 Aeruginosa
DTR CRE-KPC
P. DTRAcinetobacter
P.
Aeruginosa
878 7 Aeruginosa
DTR CRE-OXA48
Acinetobacter
DTR DTR 8 8 Acinetob
Acinetobacter CRE-MBL
• ••• Novel Plazomicin
Novel
Murepavadin •Amynoglicoside
Amynoglicoside •• Novel Plazomicin
Plazomicin
Novel Amynoglicoside Novel Novel
Cephalosporine • • Novel
Cephalosporine 6 Amynoglicoside
Plazomicin
Murepavadin
•••
Murepavadin
Plazomicin
BL/BLI
Meropenem-Vaborbactam • Tetracycline
•
• Combination
•
Murepavadin
BL/BLI •Amynoglicoside
•
Meropenem-Vaborbactam Combination • BL/BLI Novel
Ceftaroline/Avibactam •Combination
•
BL/BLI
Amynoglicoside
BL/BLI
Combination Combination
Meropenem-Vaborbactam • •
Murepavadin
Plazomicin
Murepavadin
Meropenem-Vaborbactam •
• Ceftaroline/Avibactam
BL/BLI Combination
BL CRE-KPC CRE-OXA48 •activity Meropenem/Nacubactam
Cefiderocol
Eravacyclin
Novel ESBL
Cefepime/Zidebactam •activity Eravacyclin
Eravacyclin
CRE-KPC
• Cefepime/Zidebactam ESBL ••
Cefiderocol
Cefepime/Zidebactam Meropenem/Nacubactam
Cefiderocol
Eravacyclin
•CRE-KPC
CRE-OXA48ESBL
Cefepime/Zidebactam •• P Aeruginosa
Cefepime/Zidebactam CRE-OXA48
CRE-KPC
CRE-MBL
ESBL
ESBL • • Abbreviations: Meropenem/Nacubactam
Cefiderocol
Eravacyclin
Eravacyclin
CRE-OXA48
CRE-KPC
CRE-MBL
DTR P. Aeruginosa
Cefepime/Zidebactam
6CRE-KPC
CRE-OXA48
DTR
CRE-MBL P. Aeruginosa
DTR
CRE-OXA48DTR
CRE-MBL ESBL
Acinetobacter
ESBLP. Aeruginosa
DTR CRE CRE-KPC
DTRAcinetobacter
KPC P. Aeruginosa
CRE-MBL DTRCRE CRE-OXA48
Acinetobacter
OXA48 DTR
DTR CRE CRE-MBL
Acinetobacter
MBL DTR
P Aeruginosa DTR P P. AeAeruginosa
ug nosa
DTR
••CRE-MBL DTR DTR Acinetobacter
No activity No
or activity
Nointrinsic or
or
or
No
Novel
Novel intrinsic
acquired
intrinsic
Cephalosporine Tetracycline or oracquired
resistance.
or
Novel
Novel acquired
intrinsic
Cephalosporine Tetracycline
Novel Cefiderocol
resistance.
resistance.
or Activity.
acquired
Cephalosporine Cefiderocol
Activity.
Abbreviations:
Novel resistance.
No Activity.
activity
Cephalosporine 6Activity.
Abbreviations:
BL/BLI,
or
Novel intrinsic 6 acquired
767 acquired
BL/BLI,
β-lactam/β-lactamase
Abbreviations:
or
BL/BLI,
Cephalosporine 7Inhibitor
β-lactam/β-lactamase 7 61
Novelresistance.
BL/BLI, 8β-lactam/β-lactamase
8 CRE, Inhibitor
Activity. 8 78 Abbreviations:
Inhibitor
carbapenem CRE,
CRE, 8carbapenem
6Inhibitor
8resistant
carbapenem CRE, 87resistant
8BL/BLI, 8resistant
carbapenem
β-lactam/β-lactamase resistant 88 Inhibi
••Combination Plazomicin
Plazomicin
Novel ••Combination Novel
Plazomicin
Plazomicin
Tetracycline Tetracycline
•• extended-spectrum••beta-lactamase;
Plazomicin
Ceftaroline/Avibactam No •• activity •• Novel
Novelor
2BL
Plazomicin
Novel Tetracycline
intrinsic
Ceftaroline/Avibactam 2or4•on
Tetracycline 4Cephalosporine
resistance.
23
5 24membrane
1
Activity.
3
5 42 1
Abbreviations:
5 1 BL/BLI, 4135 β-lactam/β-lactamase 3 5 protein 4 Inh
ESBL,• • metallo-β-lactamases;
BL/BLI Combination
BL/BLI Novel
Murepavadin
BL/BLI Amynoglicoside
Imipenem-Relebactam
• Eravacyclin
Aztreonam-Avibactam Novel
Murepavadin Amynoglicoside
Murepavadin
BL/BLI
Imipenem-Relebactam
Aztreonam-Avibactam Novel
Murepavadin
Combination Amynoglicoside
Aztreonam-AvibactamMeropenem/Nacubactam Ceftolozane/Tazobactam
Aztreonam-Avibactam
Novel Amynoglicoside Murepavadin
BL/BLI
Murepavadin
BL Amynoglicoside
Comb
Aztreonam-AvibactamCombination
na 2OMPTA,
Aztreonam-Avibactam 3 31.1.
Enterobacteriacae;
Enterobacteriacae;
Enterobacteriacae; ••extended-spectrum ESBL,
Enterobacteriacae;
ESBL,
Cefiderocol
Eravacyclin • extended-spectrum
• extended-spectrum
beta-lactamase;
ESBL,
Cefiderocol
Eravacyclin
Eravacyclin • Novel
• beta-lactamase;
MBLs,
Imipenem-Relebactam
Cefiderocol •
Imipenem-Relebactam Amynoglicoside
MBLs,
Enterobacteriacae;
beta-lactamase;
MBLs,
Imipenem-Relebactam
Cefiderocol • metallo-β-lactamases;
metallo-β-lactamases;
• ESBL,
MBLs,
OMPTA,
Imipenem-Relebactam
Cefiderocol
Eravacyclin OMPTA,
extended-spectrum
outer OMPTA,
membrane
• outer
outer membrane
beta-lactamase;
protein
Cefiderocol membrane targetingprotein
outerprotein
MBLs, targeting
antibiotics. antibiotics.
targeting protein
1. Decreased
antibiotics.
targeting Decreased
OMPTA,
Decreased
antibiotics. outer 1. membrane
Decreased ta
Novel BL Cephalosporine
Eravacyclin BLI Novel Combination
Novel Cephalosporine Novel
Cephalosporine Cephalosporine
Novel Enterobacteriacae;
Cephalosporine • Novel 6 ESBL,
Eravacyclin extended-spectrum beta-lactamase; MBLs, metallo-β-lactamases; OMPTA, outer membrane protein
Cephalosporine
1 6 7 1 6 7 8 1 7 8 1 6 8 8 8 7 8 8
1 1
•••carbapenemase-producing •••strains •••carbapenemase-producing •••P.strains ••ofofCR •••for
No activity No
or No
Novel
Novelintrinsic
activity
Ceftaroline/Avibactam activity
Tetracycline or
No or
Novel
Tetracycline intrinsic
acquired
Novelactivity
intrinsic
Ceftaroline/Avibactam Tetracycline
Tetracycline or
resistance.
oror acquired
intrinsic
acquired
Ceftaroline/Avibactam Novel
CRCeftaroline/Avibactam resistance.
or Activity.
acquired
No
resistance.
No
Tetracycline activity activity Abbreviations:
resistance.
Activity.
or or
Activity.
Novel intrinsic
intrinsic Abbreviations:
BL/BLI,
Activity.
or
Abbreviations:
or
Tetracycline
Ceftaroline/Avibactam acquiredacquired
Abbreviations:
BL/BLI, resistance.
resistance.
BL/BLI, β-lactam/β-lactamase
BL/BLI,Inhibitor
β-lactam/β-lactamaseActivity.
Activity. β-lactam/β-lactamase
CRE,
Abbreviations:
Inhibitor
carbapenem
Abbreviations:
Inhibitor CRE, Inhibitor
CRE, BL/BLI,
BL/BLI,carbapenem
resistant
carbapenem CRE,
resistant
carbapenem
β-lactam/β-lactamase resistant 8resista
Inh
4.Inhibi
• activity for•carbapenemase-producing
activity
activity
Ceftolozane/Tazobactamfor
for
Ceftolozane/Tazobactam ••carbapenemase-producing
activity
Plazomicin for
Murepavadin
Novel
MurepavadinAmynoglicoside
Cefepime/Zidebactam
of
Plazomicin
Novel strains
CRAmynoglicoside
Murepavadin
Murepavadin
Cefepime/Zidebactam
aeruginosa;
Plazomicin P.
2.•P.
Novel •
Cefepime/Zidebactam
aeruginosa;
strains
Very
aeruginosa;
activity
•
Amynoglicoside weakof CR2. Very
activity;
for
2.P. Very
Novel activity Amynoglicoside
Cefepime/Zidebactam
Plazomicin ••carbapenemase-producing
weak activity;
carbapenemase-producing
aeruginosa; weak
3.Ce
Not activity;
Plazomicinohave
2.ozane
Very 3.weak
3.Not
activity
Novel
Murepavadin Nothave
against
Tazobac
Amynoglicoside
Cefepime/Zidebactam
activity;
have
•strains activity
activity
am MBL;
3.ofNot against
CR4.against
have
Reduced
Novel
strains of MBL;
P. aeruginosa;
6 activity
MBL;
Amynoglicoside
CR
Cefepime/Zidebactam P. 64.against
4.
activity
aeruginosa; Reduced
2.Reduced
Very
2.against
7 MBL;
Very weak 7activity;
activity
activity
certain
weak 4. against
Reduced
against
NDM
activity; certain
3. Not
activity
83.certain
Nothave NDM
have 8against
NDM
activity certain
activity against NDM
against 8MBL; MBL; Redu
4. Re
Escherichia coliEnterobacteriacae; ••coli ••coli Cefiderocol
Murepavadin
Enterobacteriacae;
ESBL,
Enterobacteriacae; ••5.extended-spectrum
••coli Cefiderocol
Cefiderocol
Enterobacteriacae;
ESBL,
ESBL, •5. ••beta-lactamase;
Cefiderocol
extended-spectrum
extended-spectrumESBL, •extended-spectrum
Plazomicin
Cefiderocol
Meropenem-Vaborbactam Meropenem-Vaborbactam
beta-lactamase;
Enterobacteriacae;
MBLs,
Enterobacteriacae;
beta-lactamase; • isolates;
••metallo-β-lactamases; Murepavadin
Cefiderocol
beta-lactamase;
MBLs,
ESBL,
MBLs, ESBL,metallo-β-lactamases;
extended-spectrum
MBLs,
OMPTA,
extended-spectrum
metallo-β-lactamases; metallo-β-lactamases;
outer OMPTA,
to2beta-lactamase;
membrane
beta-lactamase;
OMPTA, outer protein
OMPTA,
is outer membrane
MBLs, MBLs, 6.targeting
membrane outer
protein
membrane
antibiotics.
protein targeting protein
7.targeting 1. antibiotics.
Decreased
OMPTA,
OMPTA, targeting
antibiotics. 1.
outer Decreased
antibiotics.
membrane 1.protein
Decreas
protein
Escherichia
Escherichia
isolates; 5. Novel
Eravacyclin
Activity
Escherichia
isolates; 5.Cephalosporine
Eravacyclin
isolates; comparable Activity Novel
Eravacyclin
ActivityNovel Cephalosporine
Eravacyclin
comparable
isolates;
to comparable
aztreonam Novel
Cephalosporine
Activity to
alone; Cephalosporine
Novel
Eravacyclin
toaztreonam
comparable
aztreonam 6. Activity1alone;
Cephalosporine
Escherichia
alone; 6.6.
to aztreonam
against Activity
coli
Activity Novel
Eravacyclin
OXA-type against
alone; 5.Cephalosporine
against 6.CREsOXA-type
Activity
5.Activity
OXA-type
but comparableCREs
increased
against CREs but
OXA-type increased
resistance
but aztreonam
increased
CREs resistance
observed;
resistance
but
alone; increased is
7. observed;
Activity
isNotobserved;
resistance
active 7.
against Not
against
isNot active
OXA-type
observed;
active against
against
CREs 1outer
7. CREs
Not but 1.
activemembrane
Decreased
increased
againstresistance ta
• many NDMs; • activity
many
8.
many
Nofor
No
NDMs;
Activity
activity
NDMs; ••• activity
•••activity
towardNo
No
orCeftolozane
orNo
Novel
activity
8.8.Activity
many
Activity
P.
intrinsic
activity
Imipenem-Relebactam
for
vfor
Aztreonam-Avibactam
Plazomicin
ac intrinsic
NDMs;
aeruginosa
Cefiderocol
Murepavadin
Murepavadin •••toward
activity
Tetracycline
ytoward • or
•carbapenemase-producing
or
Novel intrinsic
acquired
orfor intrinsic
Aztreonam-Avibactam
Plazomicin
8. n or
P.
Activity
andP.
Cefiderocol
Murepavadin acquired
raeruginosa
ns
aeruginosa
A.
Cefiderocol
Murepavadin •••carbapenemase-producing
Novel
activity Amynoglicoside
Imipenem-Relebactam
strains ctoward
Tazobactam
Tetracycline
orNovel
Amynoglicoside or
Plazomicin
acqu
baumannii •
resistance.
•and
Cefiderocol
or
Novelacquired
Imipenem-Relebactam
of CR P.
resistance.
and A.
P.is
Aztreonam-Avibactamred •••Novel
acquired
strains
baumannii
aeruginosa
A.overall
Cefiderocol
Murepavadin
Tetracycline
Amynoglicoside
Novel strains
Escherichia
resistance.
activity
baumannii
Aztreonam-Avibactam many of Activity.
resistance.
No
resAmynoglicoside
Imipenem-Relebactam isCR
Plazomicin
Novel
comparable
and is for
No
NDMs;
A.
activity
Imipenem-Relebactam
aeruginosa;
of activity
CR 2.
P.
strains
Very
aeruginosa;
P.
Activity.
sTetracycline
ance Tetracycline
overall
overall
baumannii
Aztreonam-Avibactam
•for
• •••8.
coli Ce
Novel
2
isolates;
6Activity.
Novel
aeruginosa;
activity
to Ac
comparable
comparable
existing
Activity
is oraz
Cefiderocol
Murepavadin2.
Plazomicin
Abbreviations:
v d
weak
of CR 2.
activity;
P. VeryyVery
Activity
Abbreviations:
Activity. Tetracycline
me
Amynoglicoside
aeruginosa;
weak
3.
intrinsic
overall Abbrev
to Av
Not
weak
existing
aminoglycosides
toward
Aztreonam-Avibactam to
2
62.4
7bac
Abbreviations:
orCeftazidime-Avibactam
intrinsic BL/BLI,
have
or
comparable
existing
P. ••aminoglycosides
comparable
Abbreviations:
oractivity;
acquired
aVery
activity;
BL/BLI, am
activity
strainsstrains
acquired
aeruginosa ons weak
3.of
aminoglycosides
6of
Not
(tobramycin,
to CR
existing
and
7toCR
4
BL/BLI,
resistance.
BL/BLI,
Imipenem-Relebactam
3.Plazomicin
Not activity;
against
have
A.have
23
aztreonam
5
activity
P. MBL;
3.
P.baumannii
aeruginosa;
resistance.
BL BL β activity
ac
(tobramycin,
aminoglycosides
amikacin,
(tobramycin,
2
aeruginosa;
am
alone;
8β-lactam/β-lactamase
6Activity.
7
Inhibitor
4against
Notagainst
4.
ishave
Reduced
3
2.5
2.Activity.
βVery
Inhibitor
6.
8activity
amikacin,
gentamicin).
overall
Activity
4acMBL;
MBL;
Very CRE,
weak
amikacin,
7
Inhibitor
Abbreviations:
activity
weak
4.
against
amase
(tobramycin,
comparableReduced
4.
3
against
8Reduced
6carbapenem
8
carbapenem
Inhibitor
4activity;
activity;
against
Abbreviations:
CRE, nh
gentamicin).MBL;
to b
gentamicin).
CRE,
5amikacin,
3BL/BLI,
OXA-type
CRE,
53.
activity
3. 8have
certain
4. Not
Not
or
existing Reduced
activity 7385against
carbapenem
4resistant
carbapenem
against
BL/BLI,have
NDM
resistant
gentamicin).
26but
activity
aminoglycosides certain
activity certain
increased
8resistant
resistant
against
NDM
against
β-lactam/β-lactamase NDM 5MBL;
(tobramycin,MBL;
resistan
8certain7Inhibi
4.8Redu
4.Inh
ND
Re
am
••coliEnterobacteriacae; many NDMs; 8. Activity toward P. aeruginosa and A. baumannii is overall comparable to existing aminoglycosides (tobramycin
Enterobacteriacae;
Escherichia
Enterobacteriacae;
ESBL,
Escherichia
ESBL, 5.•
Enterobacteriacae;
Eravacyclin
Escherichia
isolates; •coliextended-spectrum
Activity coli ESBL,
ESBL,
Eravacyclin
Escherichia
isolates; comparable
isolates; 5.an ••coli
extended-spectrum
5. extended-spectrum
Activity
Activity 5.2•
beta-lactamase;
Eravacyclin
isolates; tocomparable
aztreonam
comparable Activity beta-lactamase;
MBLs,
Escherichia
to 2 6.•metallo-β-lactamases;
Enterobacteriacae;
beta-lactamase;
to
alone;
Escherichia
comparable
aztreonam
aztreonam
Enterobacteriacae; Activity
coli •coli MBLs,
alone;
to ESBL,
MBLs,
isolates;
alone; 6.5.metallo-β-lactamases;
Eravacyclin
2ESBL,
isolates;
aztreonam
against
6Activity.6.Activity OMPTA,
extended-spectrum
3Activity
Activity
5. OXA-type
alone;
Activity 72
against
66. •comparable
comparable
against
6OMPTA,
extended-spectrum CREs 3aouter
Activity
OXA-type
butOMPTA,
membrane
beta-lactamase;
OMPTA,
toagainst
OXA-type increased
to 7CREs outer
3 MBLs
aztreonam
68OXA-type
7aztreonam
CREs
6beta-lactamase; protein
outer
but membrane
MBLs,
resistance
butincreased
alone;alone; 6.targeting
7membrane
CREs
increased
MBLs, is73
6. protein
8aobserved;
resistance
Activity
but
Activity antibiotics.
8metallo-β-lactamases;
protein
2
increased
oresistance 2targeting
targeting
against
7.is
against
8ac
metallo-β-lactamases; Not
observed;
is
8amases
6Inhibitor 1.OMPTA,
antibiotics.
resistance
activeDecreased
OXA-type
OXA-type
observed; antibiotics.
against
7.CREs
is
1. 8Decreased
8BL/BLI,OMPTA,
7resistant Not
7.
8resistant 1.
outer
observed;
CREs
Not active
but Decreased
1. membrane
but
active
outer Decreased
against
7.
increased
increased Not
against
8resistant
membrane protein
388 3active resistan
resistance again
protein ta
• • activity
Imipenem-Relebactam No CRE
Imipenem-Relebactam
No activity carbapenem
• activity
•activity Novel
No
oror
No
Plazomicin Amynoglicoside
Imipenem-Relebactam
intrinsic
activity
intrinsic
Cefepime/Zidebactam
Novel activity •extended-spectrum
Tetracycline res
Novel
Novel
orororsintrinsic
Plazomicin Amynoglicoside
Imipenem-Relebactam
acquired
acquired
Plazomicinintrinsic
Cefepime/Zidebactam
Novel No En
•Amynoglicoside
Novel
activity ••of
or
Plazomicin
beta-lactamase;
erobac
resistance.
or acquired••or
Eravacyclin
Amynoglicoside
Novel
resistance.
acquired
Plazomicin
Tetracycline Novel erintrinsic
acae
MBLs,
Eravacyclin
AmynoglicosideESBL
resistance.
Activity.
resistance.
No Activity.
oractivity
Tetracycline Novel Tetracycline
acquired ex
•weak ended
Novel
m penem
Abbreviations:
Activity.
Abbreviations:
Plazomicin intrinsicspec
Amynoglicoside
orImipenem-Relebactam
resistance.
Novel Re rum
ebac
Abbreviations:
BL/BLI,
Abbreviations:
or
BL/BLI,
acquired
Tetracycline be
•strains
am
Activity.
outer
ac
BL/BLI,
membrane
amase
resistance.
BL/BLI,
protein
Abbreviations:
Novel Tetracycline me
Inhibitor
Activity.
Inhibitor
BL/BLI,
targeting
CRE,β antibiotics.
4.Inhibitor
carbapenem
Abbreviations:
CRE,
carbapenem CRE,CRE, carbapenem
carbapenem
Inhibitor
CRE,
resistant carbapenem4.Inhibi
many
activity
for
NDMs;
for • •
8.activity
manyNovel
many for for
Cephalosporine
Activity
NDMs;
NDMs;
Murepavadin
carbapenemase-producing • toward 8.
manyNovel
Activity
8. P.NDMs;
Activity
Murepavadin strains
aeruginosa
toward •strains
Cephalosporine towardNovel •and
Murepavadinof
CR
Cefepime/Zidebactam
8. Activity P. P.CR
P.
strains
aeruginosa aeruginosa;
•P.strains
Cephalosporine
Cefepime/Zidebactam
aeruginosa
A. baumannii
toward of
Novel
and
many
aeruginosa;
CR
activity
of
P.
many
and isCR2.
P.
forVery
aeruginosa;
P.
Cephalosporine
Cefepime/Zidebactam
aeruginosa
A.
activityoverall
baumannii
NDMs;
A.2.NDMs;
baumannii
Very •for aeruginosa;
comparable
8.and8. 2.
activity;
Novel Very
2.
isActivity
A.overall
Activity
weak is
Murepavadin Very
Cefepime/Zidebactam
baumannii
overall to weak
3. Not
weakP.activity;
Cephalosporine
comparable
toward
toward
activity; existing
is have
activity;
overall
P.
comparable
3. Not
activity
3.
aminoglycosides
aeruginosa
aeruginosa
have to Not
3.of
Novel Not
comparable
existing
to
strains against
CRhave
and
existing
and
activity of A.have activity
MBL;
P.baumannii
aeruginosa;
activity
Cephalosporine
aminoglycosides
CR A.to
(tobramycin,
P.baumannii
existing
aminoglycosides
against
against
4.
aeruginosa;
MBL;
Reduced
is4.against
2.is 2. MBL;
Very
aminoglycosides
amikacin,
overall MBL;
(tobramycin,
overall
Reduced
activity
weak Reduced
4.
comparable
(tobramycin,
Very comparable
weak against
activity;
Reduced
gentamicin).
activity amikacin, activity
3.
(tobramycin,
amikacin,
tora
activity;
against
certain
toNot
activity
existing
existing
3. against
have NDM
gentamicin). against
amikacin,
gentamicin).
Not
certain
certain
activity certain
aminoglycosides
aminoglycosides
have NDM activity NDM
against
gentamicin). NDM MBL;
(tobramycin
(tobramycin,
against MBL; Redu am
4. Re
•beta-lactamase; •••Novel
OMPTA
Enterobacteriacae;
Enterobacteriacae; ••coli ou
Enterobacteriacae;
ESBL,
Enterobacteriacae;
ESBL, 5.•coli
Eravacyclin
er membrane
extended-spectrum ESBL,
extended-spectrum
Enterobacteriacae;
ESBL,5.•5.
Eravacyclin
pro
extended-spectrum
extended-spectrum
Eravacyclin
e n arge
Murepavadin
beta-lactamase; ng an
Murepavadin
beta-lactamase;
MBLs,
ESBL,Enterobacteriacae; b
extended-spectrum
beta-lactamase;
MBLs,
Eravacyclin
o
6.•metallo-β-lactamases;
cs MBLs,1
••coli ESBL,
MBLs, Decreased
6 beta-lactamase;
Eravacyclin extended-spectrumac
6OMPTA,
76•MBLs,
6.5.metallo-β-lactamases;
OMPTA,
4 v y
outer or
OMPTA,
outer carbapenemase
to6OMPTA,
7aztreonam
membrane
7CREs 8outer
65
beta-lactamase;
Eravacyclin4membrane protein
outer 7membrane
membrane
protein
MBLs,
4 OMPTA,
5 produc
8metallo-β-lactamases;
targeting
targeting
4 protein
78observed;protein
outerng 5 s
8 targeting
8membrane
4antibiotics.
6antibiotics.
targeting 5ns
81.1. 8Decreased
antibiotics.
Decreased
7protein
OMPTA, 8against
antibiotics.
57. 1.active
outer 8Decreased
Decreased
targeting
1. membrane 88 resistance
antibiotics. protein
4 1. ta D
• • Escherichia
Meropenem-Vaborbactam Escherichia
isolates;
•coli Escherichia
Plazomicin
Cefiderocol
Novel •5. Activity isolates;
•coli
Tetracycline comparable
isolates;
Plazomicin
Plazomicin
Cefiderocol
Novel •Activity
Activity
•of
Plazomicin
Cefiderocoltocomparable
aztreonam
comparable
Plazomicin
Tetracycline Novel to
alone;
aztreonam
Escherichia
to
Cefiderocol aztreonam
Tetracycline Activity
coli alone;
isolates;against
alone;
Plazomicin
Me Activity
6. OXA-type
Activity
5.Activity
orMeropenem-Vaborbactam
openem
Cefiderocol against
Vabocomparable
against CREs OXA-type
•comparable
bac but
OXA-type
am increased
Cefiderocol CREs but
resistance
butincreased
alone; increased
6. is resistance
Activity resistance 7.is
against Not
observed;
is active
OXA-type
observed; 7.CREs NotNot active
but against
increased
against
Escherichia
many
Nofor
activity
activity
NDMs;
activity
ofor2 CR many
PAztreonam-Avibactam
isolates;
No
or
aerug
Activity
many NDMs;
intrinsic
activity
••carbapenemase-producing
activity for
8.activity for
NDMs;
Murepavadin ••toward
Activity
nosa
8. 8.
2Novel
Aztreonam-Avibactam
or
No
Activity
comparable
intrinsic
acquired
Veryactivity
strains
P.activity
aeruginosa
Activity toward
Murepavadin • No
Tetracycline
weak
strains
for
Aztreonam-Avibactam
activity
toward
orNo
and
P.
Murepavadin
toac
CR
Aztreonam-Avibactam
aztreonam
resistance.
or acquired
intrinsic
P.
strains
activity
aeruginosa
P. A.aeruginosa
vstrains
of CR P.
•
baumanniior aeruginosa;
Tetracycline
Aztreonam-Avibactam
Escherichia
yintrinsic
aeruginosa;
of
activity
and
many3 of
or
alone;
3resistance.
or No
CR
and
Activity.
No
is
acquired
CR
A.
Murepavadin 2.
P.
for
2.P.
or
overall
6. Activity
activity
have
Very
aeruginosa;
Very
intrinsic
baumannii
NDMs;
A. baumannii
ac
weak
Novel
isolates;
vagainst
Abbreviations:
resistance.
Activity.
2.
aeruginosa;
acquired• strains
weak
or
comparable
8. activity;
isNovel
Activity
is of2.
acquired
Tetracycline
intrinsic
yCR
activity;
Very aga
Very
resistance.
overall
overall
Murepavadin to P.
Activity
OXA-type
Abbreviations:
weak
3. BL/BLI,
ns
weak
3. Activity.
or
Not acquired
MBL
P.activity;
have
aeruginosa;
Not
comparable
toward existing
comparableactivity;
have
resistance. •
CREs
strains
aeruginosa 2.to
Aztreonam-Avibactam
toactivity
3. Not
activity
Activity.Very
3.
aminoglycosides of
but
existingNot
CR
existing
and
to
4Abbreviations:
BL/BLI,
resistance.
Reduced
weak
Murepavadin 2
against
have
aztreonam
increased
against
have
P.baumannii
Activity. ac
activity
MBL;
aeruginosa;
activity;
activity
Abbreviations:
A. MBL;
aminoglycosides
(tobramycin,
aminoglycosides 4.
alone;
resistance
BL/BLI,Inhibitor
Activity.
vagainst
3.
is
y aga
Reduced
4.against
Abbreviations:2.
Not
Reduced
Very
BL/BLI,
6.
isns
MBL;
have
amikacin,
Activity
observed;
MBL;CRE,
weak
(tobramycin,
overall activity
BL/BLI, 4. aagainst
Inhibitor
Abbreviations:
4.cer
activity
Reduced
activity;
7.
carbapenem
Reduced
Not
ntoNDM
against
against
(tobramycin,
comparablegentamicin).
amikacin, 3.
amikacin,
OXA-type
CRE, active
NotInhibitor
BL/BLI,
activity
certain
activity
certain
MBL;
existing have
against
carbapenem
resistant
against
NDM
4.
gentamicin).
gentamicin).
CREs
CRE,
against
NDM
activity
Reduced
Inhibitor
aminoglycosides
but
3 certain
certain
increased
resistant
carbapenem
NDM
against
activity
Inhibitor
CRE, NDM MBL;
resistan
against
CRE,
carbapenem
(tobramycin,
resista
4.Inhibi
Redu
cert
carbaam
•
many
Aztreonam-Avibactam
NDMs;
• Enterobacteriacae;
Escher
Aztreonam-Avibactam
Escherichia
Escherichia ••coli
•coli
Novel
8. Eravacyclin
Activity
Novel
Escherichia
isolates;
Escherichia
isolates;
Amynoglicoside
aImipenem-Relebactam
Enterobacteriacae;
ESBL,
chAztreonam-Avibactam
co5.•coli
Cefepime/Zidebactam
toward •
Tetracycline
Activity
Novel
Eravacyclin
5.extended-spectrum
isolates;
Activity Novel
Amynoglicoside
Eravacyclin
P. aeruginosa
Enterobacteriacae;
•coli
so ESBL,
aNovel
es 5•5.
Aztreonam-Avibactam
comparable
isolates; 5.
Escherichia
comparable
Cefepime/Zidebactam
Novel Enterobacteriacae;
•
Cephalosporine
Novel
extended-spectrum
Ac
Tetracycline
Tetracycline
Activity
Activity •
Eravacyclinand
Novel
to
coli Eravacyclin
A.
beta-lactamase;
•v
ESBL,
yisolates;
comparab
comparable
to
Enterobacteriacae; aztreonam
comparable
aztreonam
Cefepime/Zidebactam
•
Amynoglicoside Novel
baumannii
Tetracycline
ESBL,
Cefepime/Zidebactam 5.
many
extended-spectrum
•Novel
beta-lactamase;
MBLs,
Enterobacteriacae;
Tetracycline
to
alone;
4
Amynoglicoside
NDMs;
is overall
eaztreonam
aztreonam
Escherichia
Activity
alone;
to
ESBL,
Cefepime/Zidebactam
extended-spectrum6. • Activity
comparable
coli
Activity
8.
•metallo-β-lactamases;
o6.extended-spectrum
az Az
Activity
Eravacyclin
comparable
beta-lactamase;
MBLs,
•reonam ESBL,
Novel
alone;
isolates;against
alone;
4
6.
against
to
to5
Amynoglicoside
toward
Tetracycline
Aztreonam-Avibactam
eonam aztreonam
Activity Av
OXA-type
Activity
OXA-type
beta-lactamase;
P.
existing
5.metallo-β-lactamases;
MBLs,
6OMPTA,
extended-spectrum
a6.Activity
one Ac
bac
4
against
comparable
against
alone;
beta-lactamase; am
CREs
CREs
5
aeruginosa Novel
aminoglycosides
6.
OXA-type
and
•MBLs,
outer
vOXA-type OMPTA, 4
tomembrane
beta-lactamase;
ybutaga ns
increased
Activity
but
MBLs, CREs
aztreonam
increased
CREs
5
Amynoglicoside
A. baumannii
(tobramycin,
outer
OXA
against protein
butOMPTA,
resistance
is
membrane
MBLs,
ype
increased
resistance
but
alone;
OXA-type
Cefepime/Zidebactam
metallo-β-lactamases; increased
6. is
5
overall
amikacin,
targeting
outer comparable
protein
isobserved;
resistance
Activity
OMPTA, observed;
CREs
gentamicin).
membrane
antibiotics.
buttargeting
CREs bu
resistance
OMPTA, ncreased
7.is
against
outer 7. Not
to
protein
observed;
increased
is
Not 1.
active
OXA-type
outer
membraneobserved;
active
4
existing 4
antibiotics.
Decreased
OMPTA, against
resistance
membrane
aminoglycosides
7.targeting
Not
against
CREs
protein 7. Not 1.isactive
outer
active
but
protein Decreased
targeting
antibiotics.
membrane
against
observed;
increased
against
targeting
5 5
(tobramycin
1.protein
Decreas
7.resistance
antibiotics. Not activ
antibiot
1. D
ta
Nofor activity No
or for intrinsic
activity
•carbapenemase-producing or
Nofor intrinsic
acquired
activity or
resistance.
or
No acquired
intrinsic
activity resistance.
oror Activity.
acquired
intrinsic
No activity Abbreviations:
resistance.
or Activity.
acquired
orVery intrinsic
Abbreviations:
resistance.
BL/BLI,
NoActivity.
or activity
acquired
Abbreviations:
BL/BLI,
or
ofActivity.
intrinsic
resistance.
3.Abbreviations:
or
BL/BLI,
acquired
Inhibitor
Activity.
resistance.
BL/BLI,
CRE,
Abbreviations:
Inhibitor
8carbapenem
CRE, Activity.
Inhibitor
BL/BLI,
carbapenem
resistant Abbreviations:
CRE,
6Inhibitor
8resistant
carbapenem CRE,
8BL/BLI,78resista
carba
Inh
β-
activity
many
manyNDMs; res
NDMs; • ance
many
8.8.Activity
many NDMs;
Activitys ••observed
Murepavadin
sactivity NDMs;
Eravacyclin
Plazomicin
Meropenem/Nacubactam toward
toward •• 8. Murepavadin
Murepavadin
activity
Activity
8. P.P. strains
7 toward
aeruginosa
Activity
many
Eravacyclinaeruginosa
Eravacyclin
Plazomicin
activity
• No
toward
NDMs; Novel •ac
forMurepavadin
•
of
and
P.
Eravacyclin
activity
Plazomicin
CR
and ve Cephalosporine
Murepavadin
Novel
P.
strains
aeruginosa
P.
8.A. •
baumannii
aeruginosa
Activity
A.
Eravacyclin
for aga Novel
Cephalosporine
aeruginosa;
of
and
baumannii
many CR
activity
nstoward
andmany
is
A.
is2.
P.Cephalosporine
strains
forVery
aeruginosa;
overall
Meropenem/Nacubactam Plazomicin baumannii
NDMs;
A.overall
P. baumannii
••aeruginosa weak
of CR
comparable
8. 6P.
Murepavadin
Novel 2.
NDMs • 8and Cephalosporine
activity;
aeruginosa;
is Plazomicin
overall
comparable
Activity
is
Eravacyclin
strains of Ac
overall
strains
CR
weak
toto 3.v Not
comparable
toward
A. existing62.
P.baumannii
7oward
yactivity;
have
comparable
ofexisting
P.
CR P.
aeruginosa;
Very
• istoactivity
strains weak
3.
aminoglycosides
aeruginosa Not
Pand
existing
aminoglycosides
overall
2.to
aeruginosa;
6comparable
CR
existing
Plazomicin
Very
7 aminoglycosides
activity;
against
have
aerug
2.A.
weak
8(tobramycin,
activity
nosa MBL;
P.baumannii Not
aeruginosa;
(tobramycin,
aminoglycosides
Very
Meropenem/Nacubactam weak
activity;
6ishave
7Reduced
toagainst
and 4. 2.
A
existing
3.
8activity
Very MBL;
baumann
amikacin,
(tobramycin,
overall
activity;
Not amikacin,
(tobramycin, 7activity;
activity
weak 4.
against 6against
Reduced s8activity
gentamicin).
3.aminoglycosides
have comparable
Not MBL;
to 3.
overa
amikacin,
gentamicin).
have
activity
activity
amikacin,
against existing 8gentamicin).
certain
4.against
Not Reduced 78 activity
against
have NDM
gentamicin).
(tobramycin,
MBL;
activity
aminoglycosides
4. MBL;
certain
amikacin,
Reduced 4. Reducedagainst
NDM
against MBL;
gentamicin).
activity
certain
(tobramycin,
activity4. Redu
against cert
ND
agaam
• • Enterobacteriacae; •coli 5.•coli • isolates;
•• activity • Enterobacteriacae; •••comparable
Cefepime/Zidebactam
Cefepime/Zidebactam
Escherichia Cefiderocol
Enterobacteriacae;
ESBL,
Cefepime/Zidebactam
Escherichia
isolates; Cefiderocol
extended-spectrum ESBL,
Cefepime/Zidebactam extended-spectrum
•coli Enterobacteriacae;
beta-lactamase;
ESBL,
•coli
extended-spectrum
•or beta-lactamase;
Enterobacteriacae;
ESBL,
MBLs, extended-spectrummetallo-β-lactamases;
beta-lactamase;
MBLs,
Ce ESBL,
5.metallo-β-lactamases;
Enterobacteriacae;
extended-spectrum
Cefepime/Zidebactam
ep me Zbeta-lactamase;
MBLs,
OMPTA,
debac 6.metallo-β-lactamases;
am outerESBL,
MBLs,
OMPTA,
beta-lactamase;
membrane
extended-spectrum
outer protein
OMPTA,
membrane
MBLs, 6.targeting
outer
beta-lactamase;
protein
OMPTA,
membrane
antibiotics.
targeting
outer protein
MBLs,
1.membrane
antibiotics.
Decreased
OMPTA,
targeting protein
1.
outer Decreased
antibiotics.
membrane
7.targeting 1.
OMPTA,
Decreas
antibiot
protein
No comparab
activity
for•carbapenemase-producing
No
orNoMeropenem-Vaborbactam
eintrinsic
activity
Murepavadin
Ceftaroline/Avibactam oActivity
activity Escherichia
isolates;
• ex sorNo
comparable
or
ng 5.activity
intrinsic
acquired
intrinsic
am
Escherichia
Murepavadin
Murepavadin
Activity
isolates;
Cefiderocol
NoEscherichia
activity
nog ortocomparable
or aztreonam
ycos
•ofNovel
Murepavadin
5.
Cefiderocol
resistance.
or acquired
intrinsic
acquired
isolates;
Murepavadin
Activity
des
•coli
to
alone;
intrinsic
isolates;
comparable
aztreonam
Escherichia
5.Cefiderocol
resistance.
or resistance.
No
obramyc
Activity
6.
Activity.
acquired
5.oractivity
Activity
Activity
coli
acquired
for•8.
nalone;
to aztreonam
or
am against
Cefiderocol
Abbreviations:
resistance. 6.
Activity.
Activity.
Murepavadin
Activity
intrinsic
resistance.
kac
comparable OXA-type
Activity
to aztreonam
alone;
against
comparable
nAbbreviations:
BL/BLI,
Activity.
Abbreviations:
or
gen
to acquired
am
aztreonam CREs
alone;
Activity
cOXA-type
Activity.n
6.
but toagainst
increased
6.CREs
aztreonam
Abbreviations:
BL/BLI,
resistance.
BL/BLI,
alone;
Activity
OXA-type
Abbreviations: but
resistance
increased
alone;
BL/BLI,
Activity
against
CREs
Inhibitor
Activity.
againstBL/BLI,
OXA-type
is observed;
resistance
but
Activity
OXA-type
CREs
increased
CRE, Inhibitor7.isNot
against
carbapenem
Abbreviations: observed;
Inhibitor
butCREs resistance
active
OXA-type
CRE,
but
increased
against
7.
Inhibitor
CRE,
BL/BLI, isInhibitor
CREs
carbapenem
resistant
increased Not
carbapenem
resistance
observed;
active
but
CRE,
resistance against
increasedisNot
resistant
carbapenem
CRE,
is observed; resistant active
resistance
carbapenem
observed; again
resista
7. NotInhibi 7. N
activ
• • activity
many Meropenem/Nacubactam
NDMs;
Enterobacteriacae; • Enterobacteriacae;
Novel
many forAmynoglicoside
Novel
8.Enterobacteriacae;
Activity
NDMs;
ESBL, toward • 8.
activity
Tetracycline Novel
many Novel
Activity
extended-spectrum
for
P.NDMs; strains
Amynoglicoside
aeruginosa
Enterobacteriacae;
ESBL, toward
Enterobacteriacae;
ESBL,
activity
Tetracycline
8. Activity
Novel
extended-spectrum and
P. CR for
P.
strains
aeruginosa
A. baumannii
toward carbapenemase-producing
aeruginosa;
Amynoglicoside
beta-lactamase;
extended-spectrumESBL, Novel
of
Tetracycline
and
many
Novel
activity
CR
Novel
P.
extended-spectrum
ESBL, is 2.
P.baumannii
strains
Very
aeruginosa;
aeruginosa
A.NDMs; Tetracycline
overall
Amynoglicoside
beta-lactamase;
MBLs,
Enterobacteriacae;
extended-spectrum
beta-lactamase;
Amynoglicoside •metallo-β-lactamases;
weak
ofActivity
CR
Me
comparable
and 2.
activity;
P.
isESBL,
A. strains
Very
overallaeruginosa;
baumannii
beta-lactamase;
MBLs,
Novel MBLs,
activity
to weak
3.
openem
Novel ofNotCR
comparable
toward existing
is
P.activity;
for
2.
have
P.Very
Nacubac
Tetracycline
overall
beta-lactamase; MBLs,
OMPTA,
extended-spectrum
Amynoglicoside
aeruginosa;
toactivity
strains
weak
3.
am
aminoglycosides
aeruginosa Not
Novel
comparable
existing
and activity;
of
against
MBLs, outer
have
2.A.
OMPTA,
CR
Veryactivity
P.MBL;
weak
3.
aeruginosa;
Notagainst
Tetracycline
aminoglycosides
membrane to
(tobramycin,
existing
baumannii
outer
beta-lactamase;
OMPTA,
4.
activity;
ishave
protein
OMPTA,
outer
Reduced
strains
2.activity
MBL;
Very
3.of
aminoglycosides
membrane
MBLs, amikacin,
membrane(tobramycin,
overalltargeting
OMPTA,
Not
activity
CR
weak
4.against
have
comparable
outer protein
Reduced
P. aeruginosa;
activity;
against
activity
gentamicin).
membrane
MBL;
amikacin, activity
(tobramycin,
antibiotics.
protein
outer
certain
3.
4.against
to existing
targeting
membrane protein
targeting
2.
Not
Reduced
Very
against
have
NDM
gentamicin).
1.OMPTA, amikacin,MBL;
weakactivity
aminoglycosides
antibiotics.
Decreased
targeting
antibiotics.
protein
certain
4.activity;
1. 1.
outer
Reduced
against
NDM
gentamicin).
Decreased
targetingantibiotics.
membrane
Decreased
3. Not
activity
certain
(tobramycin,
antibiotics.
MBL;have
1.protein
4.aga
Decreas
ND
ac
Re
1.amta
D
No activity No
orNo intrinsic
activity activity or
No many
or intrinsic
acquired
activity
intrinsic many
NDMs;
NoEscherichia
activity or orNDMs;
8. Activity
resistance.
or acquired
intrinsic
acquired or 8. Activity
toward
resistance.
or
intrinsic toward
P.
Activity.
acquired
resistance.
No oractivity aeruginosa
acquired P. aeruginosa
or and
Abbreviations:
resistance.
Activity.
Activity. A.
intrinsic
resistance. and A.
baumannii baumannii
Abbreviations:
BL/BLI,
Activity.
Abbreviations:
or acquired is overall is overall
comparable
Activity.Abbreviations:
BL/BLI,
resistance.
BL/BLI, comparable
to existing
Abbreviations: BL/BLI,Inhibitor
Activity. to existing
aminoglycosides
BL/BLI, CRE, aminoglycosides
Inhibitor
carbapenem
Abbreviations:
Inhibitor (tobramycin,
CRE, Inhibitor
CRE,
BL/BLI, (tobramycin,
carbapenem
resistant
carbapenem amikacin,
CRE,
Inhibitor amikacin,
gentamicin).
resistant
carbapenem
CRE,
resistant gentami
carbapenem resista
Inhibi
• Escherichia
• activity
Ceftaroline/Avibactam coli Novel
Escherichia
isolates;
• activity
•carbapenemase-producing Cephalosporine
5.
Eravacyclin coli
Activity Novel
Escherichia
isolates; Cephalosporine
4 activity
comparable
5.
Eravacyclin coli
ActivityNovel
isolates; to
forEravacyclin
Cephalosporine
Novel
comparable
aztreonam
5. coli
Activity
•strains Novel
Cephalosporine
isolates;
to
alone;
Eravacyclin Cephalosporine
5ofCRCR2.P.strains
Escherichia
comparable
aztreonam
5. 6.
Activity Activity coli
alone;
•weaktoisolates;
comparable
aztreonam
against
ofCe 6 6. Activity
5.
Escherichia
OXA-type
CRCeftaroline/Avibactam
a2. oCR
Eravacyclin ne Activity
alone;
to
Av aztreonam
against
6 7
bac 6. comparable
coli
CREs
Activity
•strains
am Novel
isolates;
OXA-type
alone;
but
Eravacyclin7 Cephalosporine
against
increased
to
5.6.
CREs
aztreonam
Activity
Activity
8OXA-type
but
resistance
comparable
increased
against
alone;CREs8 is6. 4
OXA-type
observed;
resistance
Activity
but
to aztreonam
increased
8 CREs
against
7.is Not
observed;
resistance
but
alone;
active
OXA-type
increased
8 6. against
7.
Activity
is Not 5
observed;
CREs
resistance
active
against
but against
7.
increased
is
Not
OXA-type
observed;
activeresistan
again
CRE
7. N
many
for•
Enterobacteriacae;
NDMs; • •Enterobacteriacae;
activity forfor
Aztreonam-Avibactam
Plazomicin
ESBL,
Enterobacteriacae;
many
8. Cefiderocol
Activity
NDMs;
•
• toward
activity
8.
many
Plazomicin
extended-spectrum
forstrains
Enterobacteriacae;
ESBL,
Enterobacteriacae;
ESBL,
Cefiderocol
Activity
P. NDMs;
aeruginosa
toward •extended-spectrum•
of
extended-spectrum
8.
manyPlazomicin
Cefiderocol
Activity and
P.
CR P.
NDMs;
strains
beta-lactamase;
ESBL, Plazomicin
Cefiderocol
aeruginosa
A. •
baumannii
toward
aeruginosa;
ESBL,
8.
of
activity
extended-spectrum
for
beta-lactamase;
MBLs,
Enterobacteriacae;
Very
aeruginosa;
P.
extended-spectrum
beta-lactamase;
Plazomicin
Cefiderocol
Activity
and P.
manyis
aeruginosa
A. overall
baumannii
toward
NDMs; •
aeruginosa;strains
2.
activity;
P.
ESBL,
MBLs,
of
Plazomicin
comparable
and
P.
8.is
Very
beta-lactamase;
MBLs,
aeruginosa;
Very weak
P.3.weak
beta-lactamase;
aeruginosa
Activity
A.overall
Notactivity;
2.
have
aeruginosa;
MBLs,
OMPTA,
extended-spectrum
Very
activity;
baumannii
to
many
comparable
toward
existing
and is
NDMs;
A.
overall
P. • MBLs,
baumannii
activity
2.weak
3.Very
aminoglycosides
aeruginosa
to
8.
Not
3.ofNotactivity;
6against
CR
outer
have
weak
OMPTA,
have
membrane
activity
6
beta-lactamase;
comparable
existing
Activity
is OMPTA,
Cefiderocol
and
overall
MBL;
3. Notagainst
P. aeruginosa;
activity;
activity
outer
outer
aminoglycosides
toward
A.to
(tobramycin,
baumannii
4.
6 have
3.
protein
OMPTA,7
MBLs,
comparable
existing
P.
Reduced
against
2.
Not
membrane
membrane
aeruginosa
activity
Very MBL;
have
OMPTA,7 MBL;
targeting
activity
weak
outer
4.against
Reduced
activity
protein
4.
7
aminoglycosides
is amikacin,
overall
(tobramycin,
to existing
and protein
outer
comparable
A.
against
activity;
6 Reduced
membrane 8 MBL;
against
antibiotics.
targeting
membrane
gentamicin).
baumannii
activity
3.
targeting
aminoglycosides
amikacin,
(tobramycin,
to
certain
4.MBL;
Not
is
Reduced
activity
8
protein
1.
against
have
7 NDM
4.
antibiotics.
Decreased
OMPTA,
existing
8
targeting
antibiotics.
protein
gentamicin).
overallamikacin,
activity
against
(tobramycin,
certain
activity
Reduced
1. 1.
outer
certain against
NDM
against
8 activity
Decreased
targeting
aminoglycosides
comparable antibiotics.
membrane
Decreased
gentamicin).
NDM 88MBL;certain
against
antibiotics.
amikacin,
to
4.8Redu
1.protein
existing Decreas
(tobramycin
gentami
ND
cert
1. ta
amino D
3 Novel
3 DTR
Escherichia •Cephalosporine
Novel5.•coli
Pseudomonas
Murepavadin
coliEscherichia
isolates;
Escherichia Cephalosporine
Activity coli Novel
Murepavadin
Escherichia
isolates;
isolates; 5.•coli
aerug
comparable
Escherichia Cephalosporine
Activity
5. isolates;
Activity nosa
Murepavadin
coli 5.•Activity
tocomparable
aztreonam
isolates;
comparable 5.Murepavadin
to
alone;
comparable
aztreonam
Escherichia
Activity
to 6.comparable
aztreonam Activity
coli • isolates;
Nove
alone;Novel
toalone;
aztreonam
against
6.5.Cepha
Murepavadin
to 6. Cephalosporine
Activity
OXA-type
aztreonam
Activity
Activity ospo
alone;
against
6.• CREs
comparable
against
alone;ne
Activity Murepavadin
OXA-type
6.but toagainst
OXA-type increased
Activity CREs
aztreonam OXA-type
CREs
against but
resistance
butincreased
alone;
OXA-type CREs
6. is
increased observed;
resistance
but
ActivityCREs increased
but7.is
resistance
against Not
observed;
resistance
increased
is active
OXA-type
observed; against
7.CREs
is
resistance Not
7. observed;
Not active
but
isactive against
7.against
observed;
increased Not 7. active
Not again
resistance activ
activity for carbapenemase-producing activity
activity
Novel
Novelforfor
Amynoglicoside carbapenemase-producing
activity
Tetracycline Novel
Novel for strains
activity
Amynoglicoside carbapenemase-producing
for
Novel
Tetracycline of CRNovel
P.
strains
carbapenemase-producingaeruginosa;
strains
Amynoglicoside of of CRCR
activity
Novel
Amynoglicoside2.
P.Amynoglicoside
strains
forVery
aeruginosa;
P. weak
of CR2. activity;
aeruginosa;strains P.
ofVery
2.aeruginosa;
CR
Very weak
P.3.weak
Notactivity;
2.have
aeruginosa;Very
activity; activity
strains2.weak
3. Not
Very
3.ofNot
Novel activity;
against
CRhave
weakhave activity
MBL;
3. Notagainst
P. aeruginosa;
activity;
activity
Amynoglicoside 4.3.
have
Reduced
against
2.
Not activity
Very MBL;
have MBL;activity
weak 4.against
Reduced
activity
4. against
activity;
Reduced MBL;
against activity
3. certain
4.MBL;
Not Reduced
activity against
have NDM
4. activity
against certain
activity
Reduced certain against
NDM
against
activityNDM MBL;certain
against4. Redu ND
cert
• • many
Cefiderocol Cefiderocol • many Cefiderocol • 8. Cefiderocol •aeruginosa•8. Ce Cefiderocol
de oco
•••Enterobacteriacae;
NDMs; 8.many
Activity
orNDMs;
NDMs; toward many
Activity
8. P. NDMs;
aeruginosa
Activity
many toward 8. Activity
toward
NDMs; and
P. aeruginosa
P.
8.
Novel A. baumannii
toward
aeruginosa
Activity and
many P.
toward
Tetracycline and is
aeruginosa
NovelA. overall
baumannii
NDMs;
A. P.baumannii comparable
and isA.overall
Activity
is baumannii
and
overall tocomparable
toward
A. existing
is
baumanniioverall
comparable
P. aminoglycosides
aeruginosaisto comparable
existing
overall
to existing
and aminoglycosides
comparable
A. to
(tobramycin,
existing
baumannii
aminoglycosides aminoglycosides
toacquired
isexistingamikacin,
(tobramycin,
overall (tobramycin, gentamicin).
aminoglycosides
comparable amikacin,
(tobramycin,
amikacin,
to existing gentamicin).
(tobramycin,amikacin,
gentamicin).
aminoglycosides
amikacin,gentamicin).gentamicin).
(tobramycin, am
6.Tetracycline
No activity No intrinsic
activity or
No intrinsic
acquired
activity or
resistance.
or
No acquired
intrinsic
activity resistance.
oror Activity.
acquired
intrinsic
No activity Abbreviations:
resistance.
or Activity.
acquired
or intrinsic
Abbreviations:
resistance.
BL/BLI,
NoActivity.
or activity
acquired
Abbreviations:
BL/BLI,
or Activity.
intrinsic
resistance.
Abbreviations:
or
BL/BLI,Inhibitor
Activity.
resistance.
BL/BLI,
CRE,
Abbreviations:
Inhibitor
carbapenem
CRE, Activity.
Inhibitor
BL/BLI,
carbapenem
resistant Abbreviations:
CRE,
Inhibitor
resistant
carbapenem CRE,
BL/BLI, resista
carba
Inh
β-
Escherichia coli Escherichia
isolates; Cefepime
5.coli Activity Escherichia
isolates; 5.Zidebactam
comparable coli
Activity
isolates; 5.Novel
tocomparable
aztreonam Activity Tetracycline
to
alone;
comparable
aztreonam Activity Novel
alone;
toalone;
aztreonam
against
6. Tetracycline
Activity
OXA-type
alone;
against
6. CREs
Activity
OXA-type
but toagainst
increased
CREs
Escherichia
Eravacyclin
coli
••Amynoglicoside
isolates;
Escherichia
Eravacyclin
5. Activity coli isolates;
comparable 5.
Escherichia
Activity
to aztreonam comparable
coli isolates; to
6 ESBL,5.6. aztreonam
Activity
Activity 6comparable
against
7alone; 6.
OXA-type
Activity 68OXA-type
7aztreonam
CREs
against
6beta-lactamase; but
resistance
butincreased
alone;
OXA-type CREs
67increased6.8is observed;
resistance
but
Activity
7outerCREs increased
resistance 7.is
against
but Not
observed;
resistance
8increased
7antibiotics.
8 targetingis active
OXA-type
observed; against
7.CREs
is
8resistance
81.membrane Not
87. observed;
Not active
but
isactive 8 against
7.against
observed;
increased
6Decreased Not 7.
8 active 8 again
resistance
Not activ
7protein
manyNovel CAmynoglicoside
Enterobacteriacae;
NDMs; Tmany
8.canNovel
Activity
many be
ESBL,
Plazomicin
NDMs;
NDMs; cons
extended-spectrum
toward 8.
many Noveldered
Enterobacteriacae;
ESBL,
Plazomicin
Activity
8. P.NDMs;
aeruginosa
Activity
many toward •extended-spectrum
8. the
Amynoglicoside
toward
NDMs; •and
Enterobacteriacae;
Eravacyclin
Plazomicin
Activity P. P.
8.most
beta-lactamase;
ESBL, Eravacyclin
Plazomicin
aeruginosa
A. •extended-spectrum
baumannii
toward
aeruginosa
Activity potent
beta-lactamase;
Enterobacteriacae;
ESBL,
MBLs,extended-spectrum
Eravacyclin
Plazomicin
and
many P.
toward
and is
aeruginosa
A.NDMs;
overall
baumannii
A. P.baumannii •metallo-β-lactamases;
agent
aeruginosa Nove
comparable
8.and A. aga
isNovel
beta-lactamase;
MBLs,
Eravacyclin
overall
Activity
is Amynog
baumannii
and
overall nst
to DTR
Amynoglicoside
comparable
toward
A. existing
is
baumannii cos
Enterobacteriacae;
extended-spectrum
beta-lactamase;
MBLs,
OMPTA,
overall
comparable
P. aeruginosa Poverall
isde
to to aerug
•aminoglycosides
outerESBL,
MBLs,
OMPTA,
membrane
Plazomicin
comparable
existing
existing nosa
aminoglycosides
andcomparable
A. to
(tobramycin, due
extended-spectrum
outer protein
OMPTA,
existing
baumannii
aminoglycosides
to
membrane
MBLs, to
targeting
aminoglycosides
isexistingamikacin, ts
(tobramycin,
overall (tobramycin, act v
beta-lactamase;
protein
OMPTA,
membrane
gentamicin).
aminoglycosides
comparable amikacin,tyexisting
outer
(tobramycin,
amikacin,
to aga
protein
MBLs, nst
antibiotics.
Decreased
OMPTA,
targeting
gentamicin).
(tobramycin,amikacin,
gentamicin).
aminoglycosides
protein
1.
outer
amikacin,
antibiotics.
membrane
targeting
gentamicin).gentamicin).
1.
OMPTA,
(tobramycin, am
Decreas
antibiot
•
activity for•carbapenemase-producing
• common
•• activity for•carbapenemase-producing
Meropenem
Murepavadin
•
Murepavadin
activity forstrains Nacubactam
activity •of CRfor
Murepavadin 6•carbapenemase-producing
P.
strains
Murepavadin aeruginosa;
of activity
CR 2.
Murepavadin P.
6strains
Very
7aeruginosa;
•• •P P
for carbapenemase-producing
weak
ofMurepavadin
CR2. activity;
P.
6strains
Very
7aeruginosa;
activity
weak
83.ofNot
CRactivity;
for
2.have
P.
6Very
7carbapenemase-producing
aeruginosa;
activity
strains
8weak
3. Notactivity;
of
against
have
2. CRVery
7 8 activity
P.8 MBL;
weak
3.
aeruginosa;
Notagainst
4.
activity;
have
Reduced
strains
8 2.activity
MBL;
Very
83.ofNot
activity
CR
weak
4.against
have
Reduced
P.
6 8aeruginosa;
activity;
6against
activity
MBL; activity
certain
3.
4.against
2.
Not
Reduced
Very
78against
have
NDM
7 MBL; weakactivity
certain
4.activity;
Reduced
against
NDM 83. Not
activity
8certain
MBL;have 4.aga
ND
ac
Re
Plazomicin Plazomicin
No activity
Escherichia resor stance
Plazomicin
Novel
No
coliEscherichia
isolates; intrinsic
activity
5.coli Tetracycline
Activity mechan
Plazomicin
Novel
or
Escherichia
isolates; intrinsic
acquired
comparable
5.activity Tetracycline
coli
Activity
Escherichia
isolates; orsms
Novel
resistance.
to acquired
comparable
aztreonam
5.activity showed
Tetracycline
Novel
coli
Activity Novel
Tetracycline
resistance.
isolates;
to
Escherichia
comparable
aztreonam
5.orby
Activity.
alone; 6.Tetracycline
Activity Activity coli aerug
alone;
Plazomicin
azom
Abbreviations:
Activity.
toisolates;
comparable
aztreonam
against
cnosa
6. Activity
5.
n
Abbreviations:
BL/BLI,
Escherichia
OXA-type
Activity
alone;
to nc
aztreonam
against
6. comparable
coli
CREs udalone;
Activity
isolates;
OXA-type
but ng
Novel
BL/BLI,
against oss
Tetracycline
increased
to
5.6.CREs
aztreonam
Activity
Activity
OXA-typeofcomparable
but outer
Inhibitor
resistance
increased
against
alone;CREs is6. membrane
OXA-typeCRE,
observed; Inhibitor
resistance
Activity
but
to carbapenem
aztreonam
increased
CREs
against CRE, por
7.β-lactam/β-lactamase
isNotobserved;
resistance
but
alone;
active
OXA-type carbapenem
resistant
increased
6. against nobserved;
7.Activity
isInhibitor
NotCREs
resistance
active
against
but resistant
against
7.
increased
isNot
OXA-type
observed;
activeresistan
again
CRE
7. N
••Tetracycline Ceftaroline Avibactam
No No activity or
No intrinsic or oror
intrinsic Noacquired
intrinsic
activity acquired resistance.
or oracquired
intrinsic
resistance. resistance.
Activity.
or acquired Activity.Abbreviations:
Activity.
resistance.
Abbreviations:Abbreviations:
BL/BLI,Activity. β-lactam/β-lactamase
BL/BLI, BL/BLI,
Abbreviations:
β-lactam/β-lactamase Inhibitor
BL/BLI, CRE, Inhibitor
carbapenem
CRE, CRE,
carbapenem resista
carba
Inhibi
Eravacyclin •toward Eravacyclin •extended-spectrum•and
Eravacyclin A.Eravacyclin • 8. Activity
Eravacyclin •aminoglycosides
Eravacyclin
(OprD)
Enterobacteriacae;
many
Novel TetracyclineNDMs;
Novel chromosoma
Enterobacteriacae;
many ESBL,
8. Activity
NDMs;
Novel extended-spectrum
8.
many ESBL,
Activity
Tetracycline AmpC
P.NDMs;
aeruginosa
Novel
Enterobacteriacae; toward
Enterobacteriacae; 8.
many
Activity
Tetracycline P.and
beta-lactamase;
Enterobacteriacae;NDMs;
aeruginosa
ESBL, baumannii
toward up-regu beta-lactamase;
and MBLs,
P.
many
extended-spectrum
ESBL, is
ESBL,
Enterobacteriacae;at
aeruginosa
A.overall
baumannii
toward
NDMs;
extended-spectrum
extended-spectrum on of
MBLs,
comparable
and
P.
8.is
Nove efflux
aeruginosa
Activity
A.overall
baumannii
Novel
beta-lactamase;
ESBL, to
many
Te pumps
comparable
toward OMPTA,
existing
and is
NDMs;
A.
overall
P.baumannii
Tetracycline
beta-lactamase; acyc
beta-lactamase;
MBLs,
extended-spectrum aeruginosa
ne to (MexXY
outer
8.comparableOMPTA,
existing
Activity membrane
isand
MBLs, MBLs, overall MexAB)
outer
aminoglycosides
toward
A.to P.protein
(tobramycin,
baumannii
comparable
existing membrane
aeruginosa
beta-lactamase; OMPTA,
MBLs, the
targeting
aminoglycosides
is OMPTA,
amikacin,
overall
(tobramycin,
to existing
and
outer except
protein antibiotics.
comparable
A. targeting
gentamicin).
OMPTA, baumannii
aminoglycosides
membrane
outer amikacin, on
(tobramycin,
outer
membraneto 1.
is be
existing
protein ng
antibiotics.
Decreased
gentamicin).
overall
membrane
OMPTA, amikacin,
(tobramycin, 1. gentamicin).
Decreased
aminoglycosides
targeting
protein comparable
protein
outer
targeting amikacin,
toantibiotics.
antibiotics.
targeting
membrane existing
(tobramycin
gentami
amino
1.protein
Decreas
antibiot
1. ta
D
• • activity
Eravacyclin for•carbapenemase-producing
Eravacyclin • activity for•carbapenemase-producing
Murepavadin
Novel
Eravacyclin
activityactivity
activity • Murepavadin
strains Cephalosporine
Eravacyclin
of CR P. strains • •of CR Murepavadin
Murepavadin P.
strains • aeruginosa;
Murepavadin
of CR 2. P. Very
aeruginosa; • •weak 2.
activity;
Very weak
Eravacyclin
E avacyc n3. Notactivity;
have • activity 3.Murepavadin
Not against
have activity MBL; against
4. Reduced MBL; activity
4. Reduced against activity
certainagainstNDM certain NDM
No activity the carbapenamase-produc
No
or intrinsic
activity or
No
for
intrinsic
acquired ng
5.activity
orstra nsactivity
resistance.
or
No acquired
intrinsicA arge
activity mu
resistance.
ororaztreonam
Activity.
acquired
intrinsic tofstrains
aeruginosa;
CR P.ofaeruginosa;
strains center CR2.P.Very
study
Abbreviations:
resistance.
or Activity.
acquired
aeruginosa;
2.weak
strains
Very
record
Abbreviations:
resistance.
activity;
2. Very
of CR
weak
P. ng weak
3. Notactivity;
the3.have
aeruginosa;
activity; nactivity
c2.Not
Very3.weak
caNot
have against
have
activity
exper activity
MBL;
activity;
against
ence 4.MBL;
against
3. NotReduced
w thMBL;
have
4. activity
4. Reduced
activity
Reduced against
against
activity activity
certain
MBL;
against aga
ND
4. Redu
cert
• • Escherichia coli
• Escherichia
isolates; 5.coli
Activity
isolates; No activity
comparable
• Escherichia Activity to or intrinsic
comparable
aztreonam to
alone;or •Activity
acquired
5.6.Activity alone; resistance.
against
coli• isolates; nBL/BLI,
6. ActivityNoActivity.
OXA-type activity
against β-lactam/β-lactamase
6. CREs
Abbreviations:
BL/BLI,
orActivity.
Activity.
OXA-type
but intrinsic
increased
6.CREs
Abbreviations:
or
BL/BLI,
Abbreviations:
but acquired
Inhibitor
resistanceβ-lactam/β-lactamase
BL/BLI,
increased resistance.
BL/BLI,
CRE,Inhibitor
carbapenem
7.β-lactam/β-lactamase
CRE,
Activity.
Inhibitor
isOXA-type
observed;
resistance isNot
observed;carbapenem
activeresistant
Abbreviations:
CRE,
7. isInhibitor
against
Not Inhibitor
active resistant
carbapenem
CRE,
against CRE,
BL/BLI,
resista
carba
carbapenem β-
th orsNo agent•Enterobacteriacae;
MurepavadinMurepavadin Murepavadin
Cefiderocol Murepavadin
coli
EscherichiaEscherichia
isolates; 5. coli
Activity
coli isolates; isolates;
5. comparable
Escherichia
Activity Mu
to
comparable Murepavadin
epavad
comparable
aztreonam
to alone;
to
5. aztreonam
Activity aztreonam
Activity
comparable
alone; 6.alone;
toagainst
Activity Activity
OXA-type
aztreonam
against against
alone; CREs
OXA-type but
6. Activity
CREsincreased
CREs
against
but resistance
but
increasedincreased
OXA-type observed;
resistance
CREs resistance
but 7. isNot
is observed;
increased observed;
active
7. Not again
7. N
resistance
Presistant
aerug
activ
nosa
activityat 22 Ita an centers under ned ts efficacy nAbbreviations:
treat
Enterobacteriacae;
many NDMs; many ESBL,
8. Activity
NDMs; extended-spectrum
Enterobacteriacae;
toward
8. ESBL,
Activity
many P. extended-spectrum
Enterobacteriacae;
beta-lactamase;
Enterobacteriacae;
aeruginosa
NDMs; toward
8.
many
ESBL,
and
P.
Activity
NDMs;
extended-spectrum
ESBL,
aeruginosa
A. baumannii
toward
beta-lactamase;
ESBL,
MBLs, extended-spectrum
extended-spectrum
and
8. many
Activityis
A.overall metallo-β-lactamases;
baumannii
P.resistance.
aeruginosa
toward
beta-lactamase;
MBLs,
comparable
P.is
Enterobacteriacae;
beta-lactamase;
overall to beta-lactamase;
MBLs,
OMPTA,
comparable
existing tong
MBLs,
aminoglycosides nfect
outerESBL,
MBLs,
OMPTA,
membrane ons
extended-spectrum
existing aminoglycosides
(tobramycin, caused
outer protein
OMPTA,
membrane targeting
OMPTA,outer
amikacin,
(tobramycin, by
beta-lactamase;
protein
OMPTA,
membrane
antibiotics.
outer targeting
outer
membrane
gentamicin).
amikacin, protein
MBLs,
1.membrane
antibiotics.
Decreased
targeting
protein
gentamicin). protein
1. Decreased
antibiotics.
targeting targeting 1.
OMPTA,
Decreas
antibiot
antibiotics. 1. D
No activity No or intrinsic
activity intrinsic
acquired or
resistance.
or
No acquired
intrinsic
activity many
resistance.
oror NDMs;
Activity.
acquired
intrinsic 8.Activity.
Activity
Abbreviations:
resistance.
or acquired toward No
NDMs;
P.
Abbreviations:
BL/BLI,
No Activity. 8.and
activity
a aeruginosa oaeruginosa
A.
Activity baumannii
or
and intrinsic
n toward
A.
vβ-lactam/β-lactamase
yAbbreviations:
BL/BLI,
Activity. and ois
baumannii
P.A.
overall
abaumannii
or
aeruginosa
nβ-lactam/β-lactamase
BL/BLI,
Inhibitor
qu comparable
acquired
is overall
ed and is overall
BL/BLI,
eCRE, to
resistance.
comparable
A.
Inhibitor
an comparable
existing
baumannii
carbapenem tois aminoglycosides
e β-lactam/β-lactamase
CRE,A toyexisting
Activity.
existing
overall
Inhibitor
carbapenem
vresistant Abb
CRE, evaminoglycosides
(tobramycin,
Abbreviations:
aminoglycosides
comparable Inhibitor
acarbapenem
on BL BL/BLI,
to existing
CRE, BL amikacin,
(tobramycin, (tobramycin,
aminoglycosides
resistant gentamicin).
amikacin,
carbapenem am amikacin,
β aβ-lactam/β-lactamase ama egentami
a gentamicin).
(tobramycin,
β resistant nhInh
bam
activityNovel
activity for carbapenemase-producing Amynoglicoside
activity forstrains
activitycarbapenemase-producing
activity
for of CRfor P.
strains
aeruginosa;
of CR 2.
carbapenemase-producing P.strains
Very
aeruginosa;
weak
of CR2.
strains activity;
P.strains
ofVery
aeruginosa;
CRactivity
weak
3.ofaeruginosa;
P. Not
CR activity;
for
2.have
P.Very
aeruginosa;
activity
2.weak
3.Very
Notactivity;
against
have
2. Very
weak activity
MBL;
weak
3. Notagainst
activity; 4.
activity;
have
3. Reduced
strains
Notactivity
MBL;
3.ofNot
have activity
CR4.against
have
Reduced
P. aeruginosa;
activity against
activity
MBL;
againstactivity
certain
4.MBL;
against
2.Reduced
Very
against
NDM
4. MBL;
weakactivity
certain
Reduced 4.activity;
Reduced
against
NDM
activity 3. Not
activity
certain
havecert
against aga
ND
ac
Enterobacteriacae;
Enterobacteriacae;
ESBL, extended-spectrum
Enterobacteriacae;
ESBL, ess
regard extended-spectrum
Enterobacteriacae;
beta-lactamase;
of ESBL,
the extended-spectrum
s te beta-lactamase;
of ESBL,
MBLs,
or extended-spectrum
gmetallo-β-lactamases;
n beta-lactamase;
MBLs,C
[31] TEn Enterobacteriacae;
beta-lactamase;
esMBLs,
oba
OMPTA,
often ESBL,
e metallo-β-lactamases;
a used
ae
outer ESBL
MBLs,
OMPTA,
membrane
as ex extended-spectrum
ended
the outer protein
OMPTA,
membrane
pe um
backbone targeting
outer beta-lactamase;
beprotein
OMPTA,
a membrane
of aantibiotics.
ama
targeting
comb outer
e protein
MBL MBLs,
1.membrane
nat antibiotics.
Decreased
onme metallo-β-lactamases;
targeting
a oprotein
therapy1.
β Decreased
antibiotics.
a ama targeting
e 1.
nvo OMPTAOMPTA,
Decreased ou outer
antibiotics.
v ng e 1.membmembrane
Decreased ane p oprotein
en a
Escherichia coliEscherichia
isolates; 5.coli
Activity
Escherichia
isolates; comparable
5. coli
Activity
Escherichia Escherichia
isolates;
tocomparable
coli aztreonam
5. coli
Activity
isolates; isolates;
to
alone;
comparable
aztreonam
5. Activity 5.6.Activity
Activity
alone;
to comparable
comparable aztreonam
against
6.
toActivity
Escherichia
OXA-type
aztreonam alone;
to aztreonam
against
6.coli
CREs
Activity
alone; isolates;
OXA-type
6.alone;
but against
increased
5.6.CREs
Activity Activity
Activity
OXA-type
but
againstresistance
comparable
increased
againstCREs
OXA-type isOXA-type
observed;
resistance
but
to aztreonam
CREs increased
CREs
but 7.is Not
observed;
resistance
but
alone;
active
increased increased
6.against
7.Activity
isNot
resistanceobserved;
resistance
active
isagainst
against
7. isNot
observed; OXA-type
observed;
active
7. Not again
CRE
7. N
activ
activity for carbapenemase-producing
activity for carbapenemase-producing
activity forstrains
activity
of CRfor P.
strains
aeruginosa;
of CR 2. P.strains
Very
aeruginosa;
weak
of CR2. activity;
P.strains
Very activity
aeruginosa;
a weak
3.of
vNot
CR for
yactivity;
2.ohave
P.Very carbapenemase-producing
aeruginosa;
a activity
bapenema
weak
3. Notactivity;
against
have
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e pactivity
odu
MBL;
weak
3. Notng against
4.
activity;
have astrains
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nMBL;
3.oNotof4.against
CR
activity
CR P P.
have
Reduced aeruginosa;
against
activity
ugMBL;
nactivity
certain 2.against
4.against
2Reduced
Ve Very
NDM
yMBL;
weakweak
activity
certain activity;
4.a Reduced
vagainst
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4 Redu
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many NDMs; many
8. Activity
NDMs; toward
8.
many
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many toward
8.
many
NDMs;Activity
and aeruginosa
8.A. baumannii
toward
Activity 8. Activity
and
toward is
aeruginosa
A.overall
baumannii
toward
P. comparable
and
P.isaeruginosa
aeruginosa A.
overall
baumannii
and A. comparable
existing
and is
NDMs;
baumanniiA.
overall
baumannii
isto
8.overall
comparable
existing
Activity
is comparable
overall
aminoglycosides
to
(tobramycin,
existing
toaeruginosa
aminoglycosides
existing amikacin,
(tobramycin,
to existing
and gentamicin).
baumannii
aminoglycosides
aminoglycosides amikacin,
(tobramycin,
is gentamicin).
overall
amikacin,
(tobramycin, (tobramycin,
comparablegentamicin).
amikacin,
togentamicin).
existinggentami
amino
Escherichia coliEscherichia
isolates; 5.coli
Activity
Escherichia
isolates;comparable
Activity Plazomicin
Escherichia
isolates;
tocomparable
aztreonam
5. coli
Activity
isolates;
alone;
comparable
aztreonam
5.6.Activity
Activity
alone;
to comparable
aztreonam
against
6. Activity
OXA-type
halone;
to aztreonam
against coli
6. CREs oisolates;
Activity
OXA-type
alone;
but
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increased
5 6.CREs
A Activity
Activity
OXA-type
v but comparable
resistance
ompa
increased
against CREsab
isOXA-type to
eobserved;
resistance
but az aztreonam
increased
eonam
CREs alone;
observed;
resistance
but
a active
oneincreased 6.
6 against
7.A Activity
isNot
observed;
vresistance
active against
n7. OXA OXA-type
observed;
active
ype 7. CREs
against
CRE Notbu but
activen increased
ea ed e resistan
against an e
many NDMs;many 8. Activity
NDMs; In th s context t s often assoc ated w th am nog ycos des co st n fosfomyc n Poss b e synerg sms
toward
8.
many
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P.
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toward
8.
many
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and
P. NDMs;
aeruginosa
A. baumannii
toward8. Activity
and
P. is
aeruginosa
A. overall
baumannii
toward comparable
andP. is
aeruginosa
A.overall
baumannii
to
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and is
NDM
A. NDMs;
overall
baumannii 8. Activity
aminoglycosides
to
8 comparable
existing
A is
v overall
y toward
aminoglycosides
owa to
(tobramycin,P.
comparable
existing
d P aeruginosa
ugaminoglycosides
n
amikacin,
(tobramycin,
to and
existing
and A A. baumannii
gentamicin).
aminoglycosides
amikacin,
um(tobramycin,
nn is overall
gentamicin).
ove amikacin,
a comparable
(tobramycin,
ompa gentamicin).
ab e o
amikacin,
o ex ex ng ng am
gentamicin).
am nog nogy oy o
de de ob ob
amy amyn amn
Novel Tetracycline
between cefto ozane tazobactam and other agents ( nc ud ng fosfomyc n co st n and am kac n) n the
• of Eravacyclin
treatment P aerug nosa are be ng stud ed n v tro and may ead to the deve opment of new treatment
opt ons• [32 33]
Murepavadin
nce No ac av ons
Ac v y Abbrev y orBLnBLI r ns cβ or acqu
ac am β red res s ance
ac amase Inh b or CRE Ac v carbapenem
y Abbrev a res onss an
BL BLI β ac am β ac amase Inh b or C
c amase MBLs me En 3erobac
a 4o CREac and
β er acae DTR
amasesESBL Acexnetobacter
OMPTA ended spec
ou er rum be apro
membrane ac eamase
n argeMBLsng anmeb ao ocsβ 1acDecreased
amases OMPTA ou er membrane pro e n arge
ac vweak
aerug nosa 2 Very y or
accarbapenemase
v y 3 No have produc
ac v ng s ra ns
y aga ns oMBLCR 4P Reduced
aerug nosaac2 vVery weak
y aga ns ac
cer va ny NDM
3 No have ac v y aga ns MBL 4 Reduced a
Cefto ozane tazobactam s nact ve aga nst carbapenemase-produc ng so ates s nce t acks act v ty
reonam a one 6 Ac v y aga ns OXA ype CREs bu ncreased res s ance s observed 7 No ac ve aga ns ype CREs bu ncreased res s ance s ob
Escher ch a co so a es 5 Ac v y comparab e o az reonam a one 6 Ac v y aga ns OXA
aga nst CPE (MIC50 90 32 >32 mg L) Moreover C T shows no act v ty aga nst meta o-β- actamases
baumann s overa many NDMs e8 Ac
comparab o exvs yngoward
am nog P ycos
aerugdes
nosa obramyc
and A baumann
n am kacs novera comparab
gen am cn e o ex s ng am nog ycos des obramyc n am kac
K pneumon ae carbapenemases or c ass D enzymes [34]
3 5 Ce taz d me Av bactam
Ceftaz d me av bactam (CAZ-AVI) s a BL BLI comb nat on of an o d cepha ospor n (ceftaz d me)
w th a new BLI (av bactam) Th s drug shows act v ty aga nst ESBL c ass C (e g AmpC) β- actamases
c ass A (e g KPC) and c ass D (e g OXA) CRE In add t on t has demonstrated act v ty aga nst some
DTR P aerug nosa so ates (Tab e 2) CAZ-AVI was approved n 2015 by the FDA for comp cated cUTI
cIAI HAP and VAP n adu t and ped atr c popu at ons Its use has a so been extended by the European
Medicines Agency (EMA) to infections due to aerobic GNB in patients with limited treatment options.
This BL/BLI combination has rapidly become one of the mainstays in the treatment of DTR-GNB
infection, and its use in real-life clinical situations has demonstrated its value in the treatment of other
clinical syndromes such as primary BSI [27].
Table 3. New antibiotics for DTR-GNB currently approved with dosing, pros and cons.
Drug Name Dosing for Patients with Normal Kidney Function Comments
PROS: rapid tissue distribution (including
lung); safe; limited activity also against
1.5 (ceftolozane 1 g + tazobactam 0.5 g) IV q 8 h iv for S.maltophilia
Ceftolozane-tazobactam UTI and IAI CONS: no activity against most anaerobes,
3 g (ceftolozane 2 g + tazobactam 1 g) IV q 8 h for NP staphylococci and enterococci; variably
susceptibility of AmpC producers, two
dosages, lower success in patients with CRRT
PROS: rapid tissue distribution (including
lung); safe; approved for empiric and targeted
therapy of DTR GNB; combination treatment
Ceftazidime-avibactam 2/0.5 g IV q 8 h with aztreonam against MBL
CONS: no activity against most anaerobes
staphylococci and enterococci; lower success
in patients with CRRT; resistance
PROS: possible activity in strains resistant to
1.25 g (imipenem 500/cilastatin 500/relebactam 250 mg) both ceftolozane/tazobactam and
Imipenem-relebactam
IV q 6 h ceftazidime/avibactam
CONS: risk of neurotoxicity
PROS: promising efficacy in the setting of
pneumonia and/or other severe KPC -CRE
infections; resistance selection overall lower
Meropenem-vaborbactam 2/2 g IV q 8 h
than ceftazidime/avibactam
CONS: not active against Amber class B or D
carbapenemases
PROS: novel siderophore cephalosporin;
promising for the treatment of DTR A.
Cefiderocol 2 g IV q 8 h (2 g IV q 6 h if CrCl > 120 mL/min) baumannii no activity also against S. maltophilia
CONS: not activity against gram positives
and anaerobes
PROS: once daily dose; carbapenem or
β-lactam/β-lactamase inhibitor sparing
alternative for UTI
Plazomicin 15 mg/kg IV q 24 h
CONS: no activity against anaerobes, A.
baumannii, S. maltophilia,; lower risk for
aminoglycosides associated toxicity
PROS: oral formulation, activity also against
gram positive (including MRSA, VRE) bacteria,
anaerobes, S. maltophilia
Eravacycline 1 mg/kg IV/oral q 12 h
CONS: suboptimal urinary pharmacokinetics;
limited data in pneumonia and BSI; no activity
against P. aeruginosa
BSI, blood stream infections; CRE; carbapenem resistant Enterobacteriales; CRRT, continuous renal replacement
therapy; DRT, difficult to treat resistance; GNB, Gram negative bacteria; IAI, intrabdominal infections;
KPC, Klebsiella pneumoniae carbapenemase producers; MBL, metallobetalactamase; MRSA, methicillin-resistant
Staphylococcus aureus; NP, nosocomial pneumonia; UTI, urinary tract infections; VRE, vancomycin-resistant
Enterococcus.
In our opinion, CAZ-AVI should be also considered as a possible therapeutic option for the
treatment of severe infections due to ESBL- or AmpC-producing species, as well as DTR P. aeruginosa.
The merits of this choice should be weighed up against those of reserving it for carbapenem-resistant
strains [35] (Tables 2 and 3).
3.6. ESBL
According to in vitro studies results, some authors have proposed the use of CAZ-AVI as a
potential carbapenem-sparing option for serious infections due to ESBL-producing Enterobacteriales.
CAZ-AVI demonstrated high in vitro potency against clinical isolates of Enterobacteriales, since it
was the most active against non-susceptible ceftazidime isolates of the comparator agents tested
(97.7% susceptibility) [36], and its effect was shown to be unchanged regardless of the ESBL enzyme
and species tested [24]. A post hoc analysis of phase 2 trials showed no differences in terms of
efficacy between ceftazidime-avibactam and carbapenems for treatment of cUTI and cIAI due to ESBL
Enterobacteriales and/or AmpC β-lactamases [37,38].
Post-marketing experience regarding the use of CAZ-AVI for infections due to ESBL-producing
Enterobacteriales remains limited. A recent real-life retrospective multicenter study in 41 patients of
the value of CAZ-AVI for the treatment of serious infections due to DTR GNB other than CRE found
excellent clinical success for ESBL (100%, 4/4), surpassing even the results obtained in the early pivotal
trials [39].
3.7. CRE
In real-life experience, high favorable response rates have been reported in patients with infections
due to KPC-producing Enterobacteriales treated with ceftazidime-avibactam, with an overall success rate
around 70% [40,41]. Among patients with KPC-KP BSI, 30-day mortality rates were significantly lower
in the ceftazidime/avibactam group than in a matched group of patients receiving other treatments
(36.5% versus 55.7%, p = 0.005) [42]. The reports of the emergence of resistance during therapy to
this new combination due to blaKPC mutations are a matter of concern. Interestingly, pneumonia
and renal replacement therapy have been associated with clinical failure and with the emergence
of resistance during therapy among patients with CRE infections [43]. Despite few clinical data,
ceftazidime/avibactam has shown promising results for salvage treatment of patients with severe
infections due to OXA-48-producing Enterobacteriales and with limited therapeutic options, with no
evidence of the emergence of resistance to ceftazidime/avibactam [44,45]. Ceftazidime/avibactam has no
activity against metallo-β-lactamase-producing Enterobacteriales (Table 2), but previous clinical studies
including patients with BSI due to MBL-producing Enterobacteriales have shown that combination
therapy with CAZ-AVI plus aztreonam is an effective therapeutic option [14].
3.8. DTR P. aeruginosa

CAZ-AVI has shown high in vitro potency against clinical isolates of P. aeruginosa collected
in European countries, including isolates that exhibit resistance to ceftazidime, meropenem and
colistin and combined resistance to agents from multiple drug classes [46]. Overall, P. aeruginosa
showed a resistance rate to CAZ-AVI ranging from 2.9 to 18% [47], and the activity of CAZ-AVI
against DTR P. aeruginosa has proven to be slightly lower than that of C/T (i.e., with lower MICs
against ESBL isolates) [48]. The use of CAZ-AVI in P. aeruginosa infections focuses on strains resistant
to C/T by the production of ESBL or class A carbapenamases and to MBL-producing strains, in
which combination treatment with aztreonam (+/−colistin) may be one of the few currently available
therapeutic options [49].
3.9. DTR Acinetobacter

Resistance to CAZ-AVI exceeds 50% in Acinetobacter baumannii, and strains isolated from patients
admitted to intensive care units (ICUs) have an even higher resistance rate, at 73.6%. In addition,
DTR Acinetobacter spp. expressing blaOXA-51 -like genes are completely resistant to CAZ-AVI [47].
4. Imipenem/Relebactam
Imipenem/relebactam is a combination of a carbapenem and a new potent non-β-lactam
β-lactamase inhibitor (relebactam). Relebactam shows activity against class A and C beta-lactamases,
but it is not active against MBL or class D carbapenemases. Imipenem/relebactam is currently approved
by FDA for the treatment of cIAI and cUTI [50,51]. Imipenem/relabactam was compared to colistin plus
imipenem in the RESTORE-IMI 1 trial, and proved to be an efficacious and well-tolerated treatment
option for carbapenem-nonsusceptible infections [52]. Currently, imipenem/relebactam is being
compared with piperacillin/tazobactam in RESTORE-IMI 2, a phase III clinical trial involving patients
with NP, including VAP [53] (Tables 2 and 3).
4.1. ESBL
The established therapeutic option for severe infections due to ESBL is a carbapenem without
a β-lactamase inhibitor. Relebactam is a non-β-lactam compound that inhibits class A enzymes,
including ESBL β-lactamases [54].
4.2. CRE
Imipenem/relebactam has a wide spectrum of activity against various phenotypes and genotypes
of carbapenem-resistant strains, especially KPC-producing Enterobacteriales. Relebactam restores
imipenem activity against carbapenem-resistant Enterobacteriales due to the impermeability caused by
the loss of the porin OprD, in association with the expression of ESBL or AmpC β-lactamase. However,
imipenem/relebactam shows no activity against MBL (VIM, IMP, or NDM) producing strains. However,
relebactam may slightly enhance the activity of imipenem against OXA-type CRE.
4.3. DTR P. aeruginosa

Relebactam restores the activity of imipenem to class A carbapenemase-producing P. aeruginosa,
and it is a poor substrate for efflux pumps. A recent study showed that it maintained activity in strains
that became resistant to both ceftolozane/tazobactam and ceftazidime/avibactam, due to AmpC or
OXA-10 mutations [55]. However, imipenem/relebactam is not active against IMP- or VIM-producing
P. aeruginosa.

Imipenem/relebactam has no activity against imipenem-resistant A. baumannii. Relebactam does
not increase the number of isolates of A. baumannii susceptible to imipenem [56].
5. Meropenem/Vaborbactam
Meropenem/vaborbactam is a fixed-dose combination product of an old carbapenem (meropenem)
with a cyclic boronic acid β-lactamase inhibitor (vaborbactam). The addition of vaborbactam to meropenem
restores its activity against Enterobacteriales producing Ambler class A carbapenemases, especially against
KPC-CRE. Vaborbactam does not inhibit Ambler class B or D carbapenemases [57]. Meropenem/vaborbactam
is FDA- and EMA0approved for the treatment of cUT Ion the strength of the TANGO I trial, and is also EMA
approved for the treatment of cIAIs and HAP including VAP [58]. The TANGO III trial for the treatment of
patients with HAP and VAP is currently ongoing [59] (Tables 2 and 3).
5.1. ESBL
The established therapeutic option for severe infections caused by ESBL is a carbapenem without
a β-lactamase inhibitor. Vaborbactam is active against serine carbapenemase, and shows potent activity
against class A EBSL, with CTX-M, TEM and SHV enzymes [60].
5.2. CRE
The TANGO II Phase 3 study supported the efficacy of M/V for the treatment of serious (cUTI, cIAI,
HAP, VAP, and BSI) infections caused by CRE, since this combination was associated with improved
clinical cure, decreased mortality, and fewer adverse events than the best available therapy in resistant
pathogens [61], and presented better results in patients without prior antimicrobial failure [62]. Despite
the paucity of data, M/V has promising efficacy in the setting of pneumonia and/or other severe
KPC producing-CRE infections in a real-world setting [57,63]. In addition, the potential for resistance
selection appears to be lower overall than that observed for CAZ/AVI and colistin. Some preclinical data
suggest that M/V in association with aztreonam could have similar activity to CAZ/AVI plus aztreonam
against CRE strains producing MBL provided that there are no OXA enzymes alongside MBL [64].
Antibiotics 2020, 9, 632 10 of 18
5.3. DTR Pseudomonas aeruginosa and DTR Acinetobacter

Vaborbactam shows no activity against Ambler class B or D carbapenemases, and it does not
improve the activity of meropenem against DTR GNB. As a matter of fact, it has no effect on meropenem
non-susceptible A. baumannii spp. producing OXA-type carbapenemases or on P. aeruginosa.
6. Cefiderocol
Cefiderocol is a novel siderophore cephalosporin which applies a “Trojan Horse” active transfer
mechanism using the bacterial iron transport system [65]. It overcomes all classes of carbapenemases,
porin channel mutations, and efflux pump overexpression. This combination of efficient cell entry and
increased stability against various types of β-lactamases makes cefiderocol highly active in vitro against
a variety of DTR GNB such as KPC and MBL-producing Enterobacteriales, P. aeruginosa-producing MBL
and A. baumannii-producing OXA-type β-lactamase, showing activity against 96% of all tested clinical
isolates [66,67].
Cefiderocol has recently (November 2019) been approved by the FDA for cUTI infections, with
limited or no alternative treatment options after demonstrating its efficacy in the APEKS-cUTI study [68].
Although the results of further clinical trials investigating the efficacy of cefiderocol for treatment
of severe infections with carbapenem-resistant GNB (CREDIBLE-CR) [69,70], NP (APEKS-NP) [71],
and BSI (GAMECHANGER) [72] are pending, recent data suggest that cefiderocol may constitute a
promising treatment option for infections caused by DTR GNB [73] (Tables 2 and 3).
6.1. ESBL
Cefiderocol shows high stability against β-lactamases, including ESBL.
6.2. CRE
The minimum inhibitory concentrations (MICs) 90 of cefiderocol have been shown to be lower
for Enterobacteriales than for nonfermenting GNB. On the basis of in vitro data, cefiderocol may
become the first-line therapy for KPC-, NDM-, VIM-, IMP-producing isolates of Enterobacteriales [74].
Several studies have analyzed the activity of cefiderocol against OXA-48-type-producing K. pneumoniae
isolates, and have reported MICs in the susceptible range (4 mg/L) [74]. Most studies have found KPC
to be susceptible to cefiderocol, while some VIM-1-producing E. cloacae strains have previously been
reported to be resistant.
6.3. DTR Pseudomonas aeruginosa

Cefiderocol has been reported to have potent in vitro activity against carbapenem-resistant
P. aeruginosa [75]. It has already been successfully used as compassionate treatment in serious infections
caused by DTR P. aeruginosa [76,77].

Cefiderocol has potential for the treatment of Acinetobacter baumannii, in which therapeutic options
are limited. It has shown potent in vitro activity against carbapenem-resistant A. baumannii [74]. On the
basis of the available data, it is not possible to establish whether one type of oxacillinase has more
activity against cefiderocol than another, but isolates of A. baumannii OXA-24/40 have shown resistance
to this antimicrobial [74].
7. Other New Antibiotics
7.1. Aztreonam/Avibactam
Aztreonam is active against MBL-producing bacteria, but is hydrolyzed by Ambler class A and
class C beta-lactamases (Table 1). Its combination with avibactam is able to inhibit cell wall synthesis
Antibiotics 2020, 9, 632 11 of 18
in MBL-producing strains, despite the presence of other co-carried beta-lactamases or carbapenemases

(Tables 1 and 2) [78]. Aztreonam/avibactam showed a potent in vitro activity against ESBL, class C
beta-lactamase, MBL, and KPC-producing strains, with a rate 10 times higher than aztreonam alone.
However, its activity against A. baumannii or P. aeruginosa compared with aztreonam alone is limited [79].
Some phase III clinical trials are temporarily suspended, though others are ongoing [80,81] (Table 2).
7.2. Plazomicin
Plazomicin is a novel aminoglycoside, with enhanced activity against ESBL-producing,
carbapenemase-producing (including metallo-β-lactamases) and aminoglycoside-resistant
Enterobacteriales. It retains stability against several aminoglycoside-modifying enzymes; however,
it is not active against many of the strains producing NDM carbapenemases. Plazomicin activity
against P. aeruginosa and A. baumannii is overall comparable to existing aminoglycosides, but is not
predictable [82]. This drug is currently FDA approved for the treatment of cUTI [83] and could be an
excellent carbapenem-sparing alternative, particularly for cUTI caused by these DTR GNB. For more
severe infections such as BSI caused by KPC Enterobacteriales, plazomicin may be administered in
individual clinical scenarios if a combination therapy is considered [84] (Tables 2 and 3).
7.3. Eravacycline
Eravacycline is a fluorocycline antibiotic in the tetracycline class with excellent in vitro activity
against GNB, including CRE, carbapenem-resistant strains of A. baumannii and S. maltophilia, but not
those of P. aeruginosa.
The FDA recently approved eravacycline for treatment of cIAIs in adults on the basis of the
results of the IGNITE 1 and IGNITE 4 [85,86] studies, but its performance was shown to be inferior to
levofloxacin and ertapenem in IGNITE 2 and 3 respectively for treating cUTI, presumably due to its
suboptimal urinary pharmacokinetics [82]. The enthusiasm regarding this drug is tempered by the
lack of clinical data on its use in pneumonia and bacteremia (Tables 2 and 3).
7.4. Murepavadin
Murepavadin is one of a new class of antibiotics called outer membrane protein targeting antibiotics,
which are highly active against DTR P. aeruginosa, as well as ceftolozane/tazobactam-resistant and
colistin–resistant strains, but it is not active against other non-fermenting GNB or Enterobacteriales.
Two clinical trials investigating the role of murepavadin in respiratory tract infections that were
prematurely terminated due to safety concerns (i.e., high rates of renal failures in the murepavadin
arm) and efficacy data for other types of infection, including BSI, are lacking (Table 2).
Below, we list several new promising antibiotics currently in development, whose clinical role
will be determined by the breakpoints assigned to them, comparison studies with other investigational
drugs, and the body of data on therapeutic outcome as they become known:
7.5. Cefepime/Zidebactam
Cefepime/zidebactam has demonstrated potent in vitro activity against DTR GNB, against
Enterobacteriales (including ESBL AmpC, KPCs, and OXA-48-producing strains), P. aeruginosa isolates
with multiple resistance mechanisms including upregulated efflux, loss of OprD porins, and AmpC
overproduction and Acinetobacter [35,87] (Table 2).
7.6. Meropenem/Nacubactam
Meropenem/nacubactam is highly efficacious against most ESBL, KPC, MBLs, AmpC, and OXA-48
producing Enterobacteriales. In addition, the combination is active against P. aeruginosa with depressed
AmpC, as well as against ESBL or AmpC-producing Enterobacteriales with porin loss. Nacubactam has
the potential to extend meropenem activity to DTR, meropenem nonsusceptible and CAZ/AVI-resistant
Antibiotics 2020, 9, 632 12 of 18
isolates. Meropenem/nacubactam has a similar activity to meropenem alone against Pseudomonas spp.
and Acinetobacter spp. [56] (Table 2).
7.7. Ceftaroline/Avibactam
The combination of avibactam with ceftaroline expands its antimicrobial spectrum covering ESBL,
KPC, and AmpC-producing strains. Nevertheless, no activity against non-fermenting bacteria has
been found [35] (Table 2).
7.8. Cefepime/Enmetazobactam
Enmetazobactam rendered cepefime active against CRE including ESBL and KPC strains in a
recent in vitro study, but its addition did not increase efficacy against P. aeruginosa [35].
Other promising agents whose activity against DTR-GNB in clinical development merit further
evaluation include taniborbactam (VNXR-5133), and pyrrolocytosines (RX-P2382), ETX2514, TP-6076,
WCK-5153, MEDI3902, COT-143.
8. Role of Combination Therapy and Duration of Treatment for DTR GNB BSI
Though the evidence available is low quality (deriving mainly from in vitro and observational
studies), empirical and target combination therapy for the treatment of CRE, DTR P. aeruginosa and
DTR Acinetobacter should be considered in the attempt to delay the emergence of antibiotic resistance,
especially in the case of severe infections (including BSI) and for critically ill patients. New antibiotics
should also be tested in studies, in association with either old antimicrobials (tigecycline, colistin,
fosfomycin, old aminoglycosides, carbapenems) and new ones [88–90].
Recent studies suggest that short-course (7-day) therapy for GNB BSI may achieve similar clinical
response and microbiological cure rates to longer courses (>7 days). However, data are lacking for
DTR GNB BSI, and longer treatment duration may be indicated in specific clinical scenarios and/or
in BSI due to particular pathogens, especially for non-fermenting GNB. Further studies are urgently
needed to test the most promising synergistic combinations and for DTR GNB BSI and to establish the
ideal treatment duration [2,91].
9. Conclusions
Resistance to currently approved antimicrobials is increasing. The armamentarium against DTR
GNB has grown, with the majority of antibiotics active against ESBL and KPC producers. However,
there is a need to prioritize MBL producers and DTR A. baumannii. Research into the development of
new antibiotics showing novel mechanisms of action should be promoted, and the implementation of
innovative trial designs should be encouraged, in order to test the new compounds against serious
infections, including BSI. In addition, a combination of antibiotics with alternative therapeutic agents
for BSI, including adjuvants, bacteriophages, antimicrobial peptides, nanoparticles, and photodynamic
light therapy, may open up interesting possibilities for future treatments.
Author Contributions: Conceptualization, M.B. writing—original draft preparation. M.P., C.S. and M.B.; writing—
review and editing, M.B., A.V., C.S., D.R.G. and M.P. All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
Antibiotics 2020, 9, 632 13 of 18
Abbreviations
BL/BLI β-lactam/β-lactamase inhibitor
BSI blood stream infections
CRE carbapenem-resistant Enterobacteriales
CAZ/AVI ceftazidime/avibactam
C/T ceftolozane/tazobactam
cIAI complicated intra-abdominal infections
cUTI complicated urinary tract infections
DTR difficult-to-treat resistance
ESBL Extended-spectrum Beta-lactamase
GNB Gram-negative bacteria
HAP hospital acquired pneumonia
IMP imipenemase
KPC Klebsiella pneumoniae carbapenemases
MBL metallo β-lactamases
MDR multidrug resistant
NDM new Delhi metallo beta-lactamase
PDR pandrug resistant
NP nosocomial pneumonia
OXA oxacillinases
VAP Ventilator associated pneumonia
VIM Verona integron-borne metallo-β-lactamase
XDR extensive drug resistance
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© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).

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antibiotics

Keywords: Gram-negative bacteria; difficult to treat bacteria; Enterobacteriales; Pseudomonas aeruginosa;

Antibiotics 2020, 9, 632; doi:10.3390/antibiotics9090632 www.mdpi.com/journal/antibiotics

2. DTR Pathogens: Mechanisms of Antibiotic Resistance and Epidemiology

2.2. ESBL-Producing Enterobacteriales

2.3. Carbapenem-Resistant Enterobacteriales

2.4. Pseudomonas aeruginosa

2.5. Acinetobacter baumannii Complex

3. Novel Treatment Options

3.8. DTR P. aeruginosa

3.9. DTR Acinetobacter

4.3. DTR P. aeruginosa

4.4. DTR Acinetobacter

5.3. DTR Pseudomonas aeruginosa and DTR Acinetobacter

6.3. DTR Pseudomonas aeruginosa

6.4. DTR Acinetobacter

7. Other New Antibiotics

in MBL-producing strains, despite the presence of other co-carried beta-lactamases or carbapenemases

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