International Journal of Antimicrobial Agents 60 (2022) 106633

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International Journal of Antimicrobial Agents

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

Clinical data from studies involving novel antibiotics to treat

multidrug-resistant Gram-negative bacterial infections
Souha S. Kanj a, Matteo Bassetti b,c, Pattarachai Kiratisin d, Camilla Rodrigues e,
María Virginia Villegas f, Yunsong Yu g,h, David van Duin i,∗
a
Division of Infectious Diseases, American University of Beirut Medical Center, Beirut, Lebanon
b
Department of Health Science, University of Genoa, Genoa, Italy
c
Infectious Diseases Clinic, Ospedale Policlinico San Martino Hospital – IRCCS, Genoa, Italy
d
Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
e
Department of Microbiology, P. D. Hinduja Hospital and Medical Research Centre, Mumbai, Maharashtra, India
f
Grupo de Investigaciones en Resistencia Antimicrobiana y Epidemiología Hospitalaria (RAEH), Universidad El Bosque, Bogotá D.C., Colombia
g
Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
h
Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Hangzhou, Zhejiang, China
i
Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA

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

Article history: Multidrug-resistant (MDR) Gram-negative bacteria (GNB) pose a critical threat to global healthcare,
Received 18 January 2022 worsening outcomes and increasing mortality among infected patients. Carbapenemase- and extended-
Accepted 26 June 2022
spectrum β -lactamase-producing Enterobacterales, as well as carbapenemase-producing Pseudomonas and
Acinetobacter spp., are common MDR pathogens. New antibiotics and combinations have been developed
Editor: Stefania Stefani to address this threat. Clinical trial findings support several combinations, notably ceftazidime–avibactam
(CZA, a cephalosporin-β -lactamase inhibitor combination), which is effective in treating complicated uri-
Keywords:
Antibiotic resistance nary tract infections (cUTI), complicated intra-abdominal infections and hospital-acquired and ventilator-
β -lactam-β -lactamase inhibitor associated pneumonia caused by GNBs. Other clinically effective combinations include meropenem–
Clinical trial vaborbactam (MVB), ceftolozane–tazobactam (C/T) and imipenem–relebactam (I–R). Cefiderocol is a re-
Gram-negative bacteria cent siderophore β -lactam antibiotic that is useful against cUTIs caused by carbapenem-resistant Enter-
obacterales (CRE) and is stable against many β -lactamases. Carbapenem-resistant Enterobacterales are a
genetically heterogeneous group that vary in different world regions and are a substantial cause of in-
fections, among which Klebsiella pneumoniae are the most common. Susceptible CRE infections can be
treated with fluoroquinolones, aminoglycosides or fosfomycin, but alternatives include CZA, MVB, I–R,
cefiderocol, tigecycline and eravacycline. Multidrug-resistant Acinetobacter baumannii and Pseudomonas
aeruginosa are increasingly common pathogens producing a range of different carbapenemases, and in-
fections are challenging to treat, often requiring novel antibiotics or combinations. Currently, no single
agent can treat all MDR-GNB infections, but new β -lactam–β -lactamase inhibitor combinations are of-
ten effective for different infection sites and, when used appropriately, have the potential to improve
outcomes. This article reviews clinical studies investigating novel β -lactam approaches for treatment of
MDR-GNB infections.
© 2022 The Authors. Published by Elsevier Ltd.
This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/)

1. Introduction these include carbapenem-resistant Acinetobacter baumannii (A.

baumannii) (CRAB), carbapenem-resistant Pseudomonas aerugi-
The World Health Organization (WHO) has classified antibiotic- nosa (P. aeruginosa) (CRPA) and carbapenem-resistant and third-
resistant bacteria into priority categories. Those ranked as crit- generation (extended-spectrum) cephalosporin-resistant Enter-
ical priority pathogens for research and development of new obacterales [1,2]. Similarly, the United States (US) Centers
antibiotics were all Gram-negative bacteria (GNB) [1] (Fig. 1); for Disease Control and Prevention (CDC) consider CRAB and
carbapenem-resistant Enterobacterales (CRE) as urgent threats
[3,4]. Multidrug-resistant (MDR) P. aeruginosa and Enterobacterales
∗
Corresponding author: Division of Infectious Diseases, CB 7030, University of
that produce extended-spectrum β -lactamases (ESBL) were also
North Carolina, 130 Mason Farm Road, Chapel Hill, NC 27599, USA.
E-mail address: david_vanduin@med.unc.edu (D. van Duin).
categorised by the CDC as serious threats [4].

https://doi.org/10.1016/j.ijantimicag.2022.106633
0924-8579/© 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
S.S. Kanj, M. Bassetti, P. Kiratisin et al. International Journal of Antimicrobial Agents 60 (2022) 106633

Fig. 1. Priority list of antibiotic-resistant bacteria, other than MDR Mycobacterium tuberculosis, for the research and development of new antibiotics.
Priority list classified by the WHO. Republished with permission of Elsevier Science & Technology journals, from Tacconelli et al. Discovery, research, and development of
new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis 2018;18:318–27 [1]; permission conveyed through Copyright Clearance
Center, Inc.

Important initiatives such as the Combating Antibiotic-Resistant with minor activity against class D β -lactamases also observed
Bacteria Biopharmaceutical Accelerator (CARB-X) global non-profit [9] (Fig. 2). In February 2015, avibactam (AVI) (in combination with
partnership, the 10 x ’20 initiative of the Infectious Diseases So- ceftazidime [CAZ]) was the first DBO to be approved by the FDA
ciety of America (IDSA) and others have partly prompted many [11]. Although activity is partner dependent (e.g. with CAZ, ceftaro-
small- and medium-sized enterprises and several pharmaceuti- line, aztreonam, cefepime or imipenem [IPM]), β -lactam-avibactam
cal companies to dedicate resources to the discovery of novel combinations are potentially highly effective against many MDR-
agents with activity against MDR-GNB [5–7]. This has resulted GNB pathogens, including Enterobacterales and P. aeruginosa, pro-
in US Food and Drug Administration (FDA) approval of several ducing class A, C, and some class D enzymes [9,12]. Switching
novel antibacterial agents. This review focuses on combinations the β -lactam partner of a clinically available β -lactamase inhibitor
of old β -lactam antibiotics with novel β -lactamase inhibitors is another approach to treat infections caused by strains that
such as ceftazidime–avibactam (CZA), meropenem–vaborbactam carry multiple classes of β -lactamases, for example the pairing of
(MVB), imipenem–relebactam (I–R), a combination of an old β - tazobactam with the novel cephalosporin, ceftolozane [9,13]. The
lactamase inhibitor with a novel anti-pseudomonal cephalosporin C/T partnership has a spectrum of activity that includes class A,
(ceftolozane–tazobactam [C/T]) and a cephalosporin with a novel- C, and some class D β -lactamases, but not carbapenemases [14].
entry mechanism of action (cefiderocol). Another DBO that has been developed is relebactam (REL), and al-
though it has a similar spectrum of activity to AVI (activity against
2. New β-lactamase inhibitors and a new β-lactam MBLs and most OXAs is lacking), greater activity against OXA-48
has been observed for AVI [15,16] (Fig. 2). Additionally, vaborbac-
The original β -lactam–β -lactamase inhibitor (BL–BLI) com- tam (VAB) (approved for use in combination with meropenem) is
binations (i.e. amoxicillin–clavulanic acid, ampicillin–sulbactam, the first FDA-approved β -lactamase inhibitor containing a cyclic
cefoperazone–sulbactam, piperacillin–tazobactam and ticarcillin– boronate pharmacophore; this forms a covalent adduct with the
clavulanic acid) were highly active against class A serine β - catalytic serine side chain of serine β -lactamases, and can inhibit
lactamases when they were introduced to the market [8,9]. Re- various class A and C β -lactamases [14,17,18].
sistance against these developed with the appearance of four Finally, cefiderocol, the first in its class, is an injectable
structurally and functionally distinct groups of β -lactamases: the siderophore cephalosporin that combines a catechol-type
metallo-β -lactamases (MBLs) of class B, AmpC serine β -lactamases siderophore and cephalosporin core with side chains like cefepime
belonging to class C, oxacillinases (OXA) – serine β -lactamases of and CAZ [19]. This structure and mechanism confer enhanced
class D and a new class A-like Klebsiella pneumoniae (K. pneumo- stability against hydrolysis by many β -lactamases, including ESBLs
niae) carbapenemase (KPC) [8,9]. As a result, a single BL–BLI part- such as CTX-M and carbapenemases such as KPC, NDM, Verona
nership with activity against all clinically important β -lactamases integron-encoded MBL (VIM), imipenem-hydrolysing MBL (IMP),
(e.g. KPC-2, OXA-23, OXA-24/40, AmpC, and New Delhi MBL-1 OXA-23, OXA-48-like, OXA-51-like and OXA-58 (Fig. 2) [19].
[NDM-1]) has been lacking, but there are some new combina-
tions such as cefepime–taniborbactam and cefepime–zidebactam
currently in development that cover a wide spectrum of these 3. Five new β-lactam approaches for various Gram-negative
enzymes and may address this need [9,10]. Diazabicyclooctanes infections
(DBO) are synthetic non-β -lactam-based β -lactamase inhibitors;
there has been an exponential expansion of this class of inhibitors, Key recent clinical studies of novel β -lactam antibiotics and
with most modifications occurring at the C2 side chain [9]. Most combinations in the treatment of MDR-GNB are summarised in
studies indicate that DBOs inhibit class A and class C β -lactamases, Table 1 .

2
 Table 1
Design and findings of key clinical studies of novel β -lactam antibiotics in combination with β -lactam inhibitors and other antibiotics in the treatment of multidrug-resistant Gram-negative bacteria.

S.S. Kanj, M. Bassetti, P. Kiratisin et al.

Trial (n) Reference Infection Investigational Design Treatment groups and Primary endpoint Results (% of patients)
drugs dose

REPROVE Torres et al. NP, including VAP CZA vs. MEM Randomised, CZA 2 g/0.5 g q8h vs. Clinical cure (at TOC Clinical cure rate, cMITT
n =726 (cMITT), 2018 [24] double-blind, MEM 1 g q8h. visit) CZA: 68.8% MEM:73.0%
n = 527 (CE) Phase III Duration: 7–14 days Clinical cure rate, CE
non-inferiority CZA: 2 h-infusion, MEM: CZA: 77.4% MEM:78.1%
30-min infusion (CZA non-inferior in the treatment of NP)
ASPECT-NP Kollef et al. Ventilated NP C/T vs. MEM Randomised, C/T 3 g q8h vs. MEM 1 g 28-day all-cause C/T: 24.0%
n = 726 (ITT) 2019 [44] controlled, q8h. mortality in ITT MEM: 25.3%
double-blind, Duration: 8–14 days, population (C/T non-inferior for 28-day mortality)
Phase III both given by 1-h
non-inferiority infusion
ASPECT-cIAI Solomkin cIAI C/T + MZL vs. Randomised, C/T 1.5 g + MZL 500 mg Clinical cure at TOC in Clinical cure at TOC in microbiological ITT
n = 806 et al. 2015 MEM prospective, q8h vs. MEM q8h. microbiological ITT population
(microbiological [45] double-blind, Duration: 4–14 days population C/T + MZL: 83%
ITT) non-inferiority MEM: 87.3%
Clinical cure at TOC in microbiologically
evaluable (secondary) population
C/T + MZL:
94.2%
MEM: 94.7%
(prespecified non-inferiority margin met)
ASPECT cUTI Complicated lower C/T vs. LVX Randomised, C/T 1.5 g q8h vs. LVX 750 Composite of C/T: 76.9%
n = 800 (mMITT) Wagenlehner UTI or pyelonephritis double-blind, mg OD. microbiological LVX: 68.4%
et al. 2015 double-dummy, Duration: 7 days eradication and clinical (C/T non-inferior to LVX for composite cure)
[46] non-inferiority cure 5–9 days post
treatment in mMITT
population
TANGO I Kaye et al. cUTI, including acute MVB vs. PPN–TAZ Randomised, MVB (2 g/2 g over 3 h) FDA: Overall success FDA endpoint, overall success
3

n = 374 2018 [116] pyelonephritis multicentre, vs. PPN–TAZ (4 g/0.5 g (clinical cure or MVB: 98.4%
(microbiological double-blind, over 30 min) q8h for 15 improvement and PPN–TAZ: 94.0%
mITT population) double-dummy, doses. microbial eradication EMA endpoint (microbiological mITT):
n = 347 active-control, Mean duration, IV and composite) at end of IV MVB: 66.7%
(microbiological Phase III oral stepdown therapy: treatment in PPN–TAZ: 57.7%
evaluable 10 days microbiological mITT EMA endpoint (microbiological evaluable):
population) population MVB: 66.3%
EMA: microbial PPN–TAZ: 60.4%
eradication at TOC visit (non-inferiority criterion met)

International Journal of Antimicrobial Agents 60 (2022) 106633

in the microbiological
mITT and microbiological
evaluable populations
TANGO II Wunderink Carbapenem-resistant MVB vs. BATb Randomised MVB (2 g/2 g over 3 h, Clinical cure, Day 28 Cure rate at end of treatment
n = 47 et al. 2018 Enterobacterales controlled, q8h for 7–14 days) vs. all-cause mortality, MVB: 65.6%
(mCRE-MITT) [36] infectionsa multinational, BAT microbiological cure, and BAT: 33.3%
open-label, overall success (clinical Cure rate at TOC:
Phase III cure + microbiological MVB: 59.4%
eradication) BAT: 26.7%
Day 28 all-cause mortality
MVB: 15.6%
BAT: 33.3%
APEKS-cUTI Portsmouth cUTI +/- CDL vs. IPM Phase II, CDL 2 g q8h vs. IPM Composite clinical and Microbiological eradication at TOC in mITT
n = 371 (mITT) et al. 2018 pyelonephritis or multicentre, (imipenem/cilastatin 1 microbiological outcomes population
[51] acute uncomplicated double-blind, g/1 g) q8h. at TOC (7 days after CDL: 73%
pyelonephritis parallel-group Duration: 7–14 days treatment end) IPM: 56 %
non-inferiority Clinical response rate at TOC in mITT
population
CDL: 90%
IPM: 87%
(prespecified non-inferiority margin met)
(continued on next page)
 S.S. Kanj, M. Bassetti, P. Kiratisin et al.
Table 1 (continued)

Trial (n) Reference Infection Investigational Design Treatment groups and Primary endpoint Results (% of patients)
drugs dose

APEKS-NP Wunderink Hospital-acquired CDL vs. MEM Randomised, 3 h IV infusion CDL 2 g All-cause mortality at CDL: 12.4%
n = 292 (mITT) 2021 et al. ventilator-associated double-blind, q8h vs. MEM 2 g q8h. Day 14 in mITT MEM: 11.6%
[52] or parallel-group, Duration 7–14 days population (prespecified non-inferiority margin met)
healthcare-associated Phase III,
Gram-negative non-inferiority
pneumonia
CREDIBLE-CR Bassetti Life-threatening CDL vs. BAT Randomised, 3 h IV infusion CDL 2 g For NP, BSI and sepsis, NP, clinical cure
n = 118 (CR-MITT) et al. 2021 carbapenem-resistant open-label, q8h vs. BAT. clinical cure at TOC in CDL: 50%
[53] Gram-negative multicentre, Duration 7–14 days the CR-MITT. For cUTI, BAT: 53%
infections parallel-group, microbiological BSI/sepsis, clinical cure
pathogen- eradication at TOC in the CDL: 43%
focused, CR-MITT BAT: 43%
descriptive, cUTI, microbiological eradication
Phase III CDL: 53%
BAT: 20%
(CDL similar efficacy to BAT)
RESTORE-IMI 1 Motsch et al. Hospitalised patients I–R vs. IPM + CST Multicentre, I–R (500 mg/250 mg, Favourable overall Favourable overall response
n = 31 (mMITT) 2020 [117] with randomised, q6h) vs. IPM (500 mg response (defined by I–R: 71%
HAP/VAP, cIAI or cUTI controlled, q6h) + CST (loading dose relevant endpoints for IPM + CST: 70%
caused by double-blind, 300 mg, then each infection) in mMITT Day 28 all-cause mortality
IPM-resistant Phase III maintenance doses up to population I–R: 10%
pathogens 150 mg, q12h) IPM + CST: 30%
Duration: 5–21 days
RESTORE-IMI 2 Titov et al. HABP or VABP I–R vs. PPN–TAZ Multicentre, I–R (500 mg/500 mg/250 Day 28 all-cause Day 28 all-cause mortality
4

n = 531 2020 [38] randomised, mg) vs. PPN–TAZ (4 mortality in mITT I–R: 15.9%
(mITT) controlled, g/500 mg) q6h. Duration: population PPN–TAZ: 21.3%
double-blind, 7–14 days Favourable clinical response at early
Phase III follow-up
I–R: 61.0%
PPN–TAZ: 55.8%
Dose-ranging study Lucasti et al. cIAI REL (2 doses) vs. Randomised, REL (125 mg), REL (250 Proportion of ME pts Favourable clinical response at DCIV
n = 255 2016 [39] PBO (all + IPM) multicentre, mg), PBO, IV (all + IPM with a favourable clinical REL 250 mg: 96.3%
(ME at DCIV) double-blind, 500 mg) q6h. response at DCIV REL 125 mg: 98.8%

International Journal of Antimicrobial Agents 60 (2022) 106633

controlled trial Duration 4–14 days PBO (IPM alone): 95.2%
(both IPM plus REL doses non-inferior to
IPM alone)
Dose-ranging, Sims et al. cUTI or acute REL (2 doses) vs. Randomised, REL (125 mg), REL (250 Favourable Favourable microbiological response rate
comparative trial 2017 [118] pyelonephritis PBO (all + IPM) multicentre, mg), PBO (all + IPM 500 microbiological response I–R (REL 250 mg): 95.5%
n = 230 double-blind, mg), 30 min IV infusions rate (pathogen I–R (REL: 125 mg): 98.6%
(ME at DCIV) controlled, q6h. eradication) at DCIV in IPM alone: 98.7%
non-inferiority, Duration 4–14 days ME population (IMI-REL with both REL doses non-inferior to
Phase II IPM alone)
dose-ranging
a
Bacteraemia, HABP/VABP, cIAI, cUTI/acute pyelonephritis)
b
BAT, best available therapy including mono/combination therapy with polymyxins, carbapenems, aminoglycosides, tigecycline, or ceftazidime–avibactam alone.BAT, best available therapy; BSI, bloodstream infection;
C/T, ceftolozane–tazobactam; CE, clinically evaluable; CDL, cefiderocol; cIAI, complicated intra-abdominal infection; cMITT, clinically modified intention-to-treat (population); CR, carbapenem-resistant; CRE, carbapenem-
resistant Enterobacterales; CR-MITT, carbapenem-resistant microbiological ITT (population); CST, colistin; cUTI, complicated urinary tract infection; CZA, ceftazidime–avibactam; DCIV, discontinuation of IV therapy; EMA,
European Medicines Agency; FDA, US Food and Drug Administration; HAP, hospital-acquired pneumonia; HABP, hospital-acquired bacterial pneumonia; IPM, imipenem; I–R, imipenem-cilastatin-relebactam; ITT, intent-to-
treat (population); IV, intravenous; LVX, levofloxacin; MEM, meropenem; MVB, meropenem–vaborbactam; mCRE-MITT, microbiologic-CRE modified intent-to-treat (population); ME, microbiologically evaluable; mITT: modified
intent-to-treat (population); mMITT, modified microbiological intent-to-treat (population); MZL, metronidazole; NP, nosocomial pneumonia; OD, once daily; PBO, placebo; pt: patient; PPN–TAZ, piperacillin–tazobactam; q6h,
every 6 hours; q8h, every 8 hours; q12h, every 12 hours; REL, relebactam; TOC, test of cure; UTI, urinary tract infection; VAP, ventilator-associated pneumonia; VABP, ventilator-associated bacterial pneumonia.
S.S. Kanj, M. Bassetti, P. Kiratisin et al. International Journal of Antimicrobial Agents 60 (2022) 106633

Fig. 2. A) Activity of avibactam, tazobactam, vaborbactam and relebactam against important β -lactamases within different classes; and B) stability of cefiderocol against
these enzymes [16,19,50,143,144].
ESBL, extended-spectrum β -lactamase; KPC, Klebsiella pneumoniae carbapenemase; MBL, metallo-β -lactamase; OXA, oxacillinase.
∗
Enhanced stability to β -lactamases does not always correlate with clinical efficacy.

3.1. Ceftazidime–avibactam (CZA) 3.2. Meropenem–vaborbactam (MVB)

The combination CZA is an intravenously administered for- Intravenous MVB was the first carbapenem–β -lactamase
mulation of the extended-spectrum cephalosporin CAZ and the inhibitor combination approved in the US for use in pa-
novel, non-β -lactam β -lactamase inhibitor AVI [20]. Ceftazidime– tients with cUTI, including pyelonephritis [18,29]. One compo-
avibactam has potent activity against Enterobacterales carrying nent, meropenem, is active against MDR bacteria, except for
blaKPC and blaOXA-48 and the activity of this combination also ex- carbapenemase-producing strains [18]. The other component, VAB,
tends to MDR P. aeruginosa [16,21]. It is approved in many coun- is a potent inhibitor of class A serine carbapenemases and restores
tries for the treatment of adults and paediatric patients (≥ 3 meropenem activity against class A and class C carbapenemases,
months) with cUTI, including pyelonephritis [22,23], complicated but not against class B or class D carbapenemases [30]. It also
intra-abdominal infections (cIAI) [22,23], hospital-acquired pneu- restores the activity of meropenem against β -lactamase-producing
monia (HAP) including ventilator-associated pneumonia (VAP) [24], Enterobacterales, including KPC- and ESBL-producers [29,31]. It
and other infections caused by aerobic MDR-GNB in patients with may be an alternative for KPC-producing Enterobacterales but
limited treatment options [22,25,26]. The efficacy and safety of CZA has no effect on other MDR bacteria such as A. baumannii [30].
has been studied in five Phase III clinical trials. In the RECAPTURE Meropenem has good activity against most P. aeruginosa strains
study (CZA versus Doripenem for the Treatment of cUTI, Including but not those that have porin mutations or overproduce efflux
Acute Pyelonephritis), CZA was non-inferior to doripenem and both pumps, and VAB does not restore this activity [32–34]. Of note,
treatments showed similar efficacy against CAZ-non-susceptible some CZA-resistant KPC-3 variants (e.g. V240G and D179Y) have
pathogens [26]. The REPRISE study was a pathogen-directed, in- increased susceptibility to meropenem [35], and thus susceptibility
ternational study of 333 patients with cUTI or cIAI caused by to MVB would be expected.
CAZ-resistant Enterobacterales or P. aeruginosa who were treated In the Phase III, non-inferiority Targeting Antibiotic Non-
with CZA or best available treatment (BAT) [22]; clinical cure Susceptible Gram-negative Organisms (TANGO I) trial in patients
rates were similar between the two treatment arms (91% in both with cUTIs, intravenous MVB was found to be non-inferior to
groups). intravenous piperacillin–tazobactam for overall success [29]. The
In another study, CZA plus metronidazole was found to be non- TANGO II trial evaluated the safety and tolerability of MVB alone
inferior to meropenem in clinical cure at test of cure (TOC) and and MVB in combination with a polymyxin (colistin), high-dose
30-day all-cause mortality in the treatment of cIAIs. The efficacy meropenem, CZA (n = 1), or an aminoglycoside versus BAT in pa-
of this combination was similar against infections caused by CAZ- tients with serious CRE infections [36]. Meropenem–vaborbactam
susceptible and CAZ-resistant pathogens [22,24]. In the case of was associated with increased clinical cure, decreased mortality
HAP and VAP, CZA was found to be non-inferior to meropenem and reduced nephrotoxicity compared with BAT [36]. The use of
in terms of clinical cure rates and 30-day all-cause mortality MVB for treating HAP, including VAP, has been approved by the
[24]. European Medicines Agency (EMA) [37].
Several studies have assessed the spectrum of activity and the
efficacy of CZA in the treatment of infections due to MDR-GNB 3.3. Imipenem–relebactam (I–R)
[14]. A meta-analysis showed in 12 studies that this combination
had a pooled clinical success rate of 73% (95% CI 67.7–78.4%) in Imipenem–relebactam, a novel BL–BLI combination, was re-
treating CRE and MDR P. aeruginosa infections (mainly pneumo- cently approved for the treatment of cUTI, cIAI, HAP and VAP [38].
nia) [14]. Based on this evidence, the UK Clinical Pharmacy As- Relebactam is a β -lactamase inhibitor with the ability to inhibit
sociation recommends CZA for the treatment of KPC- and OXA- a broad spectrum of β -lactamases such as class A and class C β -
48-producing Enterobacterales [27]. In addition, a recent observa- lactamases, including carbapenemases [39]. The addition of REL to
tional study showed a therapeutic advantage for CZA in combina- IPM restores IPM activity against several IPM-resistant bacteria, in-
tion with aztreonam compared with other active antibiotics in pa- cluding MDR P. aeruginosa and Enterobacterales such as CRE KPC
tients with bloodstream infections (BSI) due to MBL-producing En- producers [39,40]. Imipenem–relebactam has also shown clinical
terobacterales [28]. activity against several other aerobic (Escherichia coli, Enterobac-

5
S.S. Kanj, M. Bassetti, P. Kiratisin et al. International Journal of Antimicrobial Agents 60 (2022) 106633

ter cloacae, amongst others) and anaerobic Gram-negative bacteria,

and it is also active against Enterococcus faecalis and methicillin-
susceptible Staphylococcus aureus [40]. However, REL-IPM is inac-
tive against MBL-producing Enterobacterales and CRAB [40]. In the
RESTORE-IMI 1 trial, the efficacy of I–R was found to be compa-
rable with that of colistin–imipenem for treating infections caused
by IPM-non-susceptible GNB in patients with HAP and VAP, cUTI
and cIAI; the incidence of nephrotoxicity was significantly lower
for I–R. In addition, the RESTORE-IMI 2 trial demonstrated non-
inferiority of I–R to piperacillin–tazobactam in the treatment of
HAP and VAP [38,40]. A recent open-label, noncomparative, Phase
III study examined the efficacy of I-R amongst hospitalised patients
requiring intravenous antibiotics for cIAI and cUTI, including pa-
tients with secondary sepsis. At the end of treatment, 85.7% of pa-
tients with cIAI and 100.0% of patients with cUTI achieved clinical
or microbiological responses, respectively, and a favourable com- Fig. 3. The mechanism of action of cefiderocol.
posite clinical and microbiological response was reported for those Republished with permission of Sage Publications Inc. Journals, from El-
with sepsis [41]. Lababidi and Rizk. Cefiderocol: A Siderophore Cephalosporin. Ann Pharmacother
2020;54:1215–31 [145]; permission conveyed through Copyright Clearance Center,
Inc.
3.4. Ceftolozane–tazobactam (C/T)
has better stability to a variety of β -lactamases, including AmpC,
The C/T combination contains a cephalosporin (ceftolozane) and
ESBLs and MBLs [50].
a β -lactamase inhibitor (tazobactam), and shows in vitro activity
Cefiderocol was compared, in a Phase II, multicentre, non-
against a broad range of GNB, including ESBL-producing strains of
inferiority trial, with imipenem–cilastatin for the treatment of cUTI
Enterobacterales and P. aeruginosa, and MDR or extensively drug-
in hospitalised adults at risk of MDR Gram-negative infections. At
resistant (XDR) P. aeruginosa [13,42]; however, C/T is not active
TOC (7 days after treatment cessation), 73% patients treated with
against CRE [13]. Ceftolozane–tazobactam has been approved for
cefiderocol and 55% of patients treated with imipenem-cilastatin
the treatment of cUTI, including pyelonephritis, cIAI (in combina-
achieved the composite endpoint of clinical and microbiological re-
tion with metronidazole), HAP and VAP in adults [43].
sponse, with a significant (18.6%) treatment difference in favour of
In the ASPECT-NP trial, C/T was compared with meropenem
cefiderocol [51]. In turn, the Phase III, non-inferiority trial APEKS-
for treatment of nosocomial pneumonia, and showed that 3 g
NP evaluated the efficacy and safety of cefiderocol vs. high-dose
q/8 hours of C/T is an effective and well-tolerated treatment for
meropenem for the treatment of adults with Gram-negative noso-
GNB nosocomial pneumonia in mechanically ventilated patients,
comial pneumonia [52]. All-cause mortality at day 14 was 12.4%
which is a high-risk, critically ill population [44]. Post hoc anal-
for cefiderocol and 11.6% for meropenem, demonstrating non-
ysis showed lower mortality for C/T compared with meropenem
inferiority for cefiderocol; similar tolerability was reported [52].
in the subgroup of patients with ventilated HAP; however, signifi-
The CREDIBLE-CR study compared efficacy and safety of cefidero-
cance was not demonstrated and additional analyses are planned.
col vs. BAT for the treatment of serious infections caused by CR-
Lower mortality for C/T was also observed for the subgroup of
GNB. Cefiderocol and BAT had comparable clinical and microbio-
those failing prior antibiotic therapy [44]. The Phase III randomised
logical efficacy in a heterogeneous patient population [53]. How-
trial (ASPECT-cIAI) compared the efficacy of C/T plus metronidazole
ever, numerically more deaths occurred in the cefiderocol group,
vs. meropenem for the treatment of cIAI. In this study, C/T plus
primarily in the patient subset with P. aeruginosa infections, and
metronidazole demonstrated non-inferiority to meropenem, with
more so with Acinetobacter spp. infections. The IDSA guidance sug-
clinical cure rates of 95.8% and 88.5%, respectively, in patients with
gests that cefiderocol can be considered in urinary tract infections
ESBL-producing Enterobacterales [45]. The Phase III, ASPECT-cUTI
(UTI) caused by CRE [54]. Additional data on the efficacy of cefide-
study was a large, international trial evaluating C/T vs. high-dose
rocol compared with standard therapy for healthcare-associated
levofloxacin for the treatment of cUTIs, including pyelonephritis.
and hospital-acquired Gram-negative bloodstream infections is ex-
Five to nine days after treatment, C/T and levofloxacin achieved
pected to emerge from the Phase II, investigator-driven GAME
composite cure rates (microbiological eradication and clinical cure)
CHANGER trial, which is due to report in March 2023 [55].
of 76.9% and 68.4%, respectively, indicating superior efficacy for
C/T in this setting [46,47]. Strains of P. aeruginosa that are non-
4. Clinically important β-lactam-resistant Gram-negative
susceptible to piperacillin–tazobactam, CAZ or meropenem are less
pathogens
likely to be susceptible to other β -lactams but are more likely
to be susceptible to C/T [48]. However, more evidence is needed
An overview of antibiotic-resistant GNB pathogens is given in
to confirm its exact role in treating infections caused by ESBL-
Table 2, detailing the most clinically relevant drugs to which key
producing Enterobacterales [49].
pathogens such as K. pneumoniae, A. baumannii and P. aeruginosa
are resistant.
3.5. Cefiderocol
4.1. ESBL-producing Enterobacterales
As with other β -lactam antibiotics, the principal antibacte-
rial/bactericidal activity of cefiderocol occurs by inhibition of cell ESBL-producing Enterobacterales are a major group amongst
wall synthesis by binding to penicillin-binding proteins; however, antibiotic-resistant GNB, and are responsible for significant mor-
it is unique in that it enters the bacterial periplasmic space be- bidity and mortality [56–58]. The incidence of infections with
cause of its siderophore-like property (Fig. 3) [19,50]. The chemical ESBL-producing Enterobacterales is rapidly increasing worldwide
structure of cefiderocol is similar to both CAZ and cefepime, which and is an evolving crisis [59]. In the US, the incidence of ESBL-
are third- and fourth-generation cephalosporins, respectively, but producing Enterobacterales infections increased by 53% from 2012

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S.S. Kanj, M. Bassetti, P. Kiratisin et al. International Journal of Antimicrobial Agents 60 (2022) 106633

Table 2
Multidrug-resistant Gram-negative pathogens – key drugs and characteristics.

Pathogen Key drug resistance Classification of threat [1,2,119] Common Remarks

infections/setting

Non-fermenting Gram-negative bacteria

Acinetobacter BLs (e.g. cephalosporins, Carbapenem-resistance: critical BSI, UTI, IAI, A. baumannii is an increasing threat worldwide. It
baumannii carbapenems), tetracyclines threat meningitis, HAP, is an environmental pathogen that produces
(e.g. tigecycline), colistin, VAP biofilms enhancing bacterial survival despite
fluoroquinolones treatment. Infections can be difficult to treat and
are associated with high costs, significant
morbidity and mortality, especially in ICU patients
[89]
Pseudomonas BLs, carbapenems, Carbapenem-resistance: critical VAP/HAP, BSI, CF, P. aeruginosa is a common environmental pathogen
aeruginosa fluoroquinolones, polymyxins, threat UTI, wound, burn that develops biofilms and is strongly associated
aminoglycosides, fosfomycin, with respiratory infections, especially in CF.
rifampin Intrinsically resistant to antibiotics due to low
membrane permeability, efflux pumps and
β -lactamases [108,120,121]
Enterobacterales
Escherichia coli BLs (e.g. third- and fourth- Carbapenem-resistance: critical GI, UTI, HAI, Most commonly isolated GNB pathogen in multiple
generation cephalosporins, threat neonatal different infection sites. High rates of resistance
carbapenems), Third-generation meningitis and multi-resistance to antibiotics. Common cause
fluoroquinolones, polymyxins, cephalosporin-resistance: of HAI [122–124]. E. coli, K. pneumoniae and P.
aminoglycosides critical threat aeruginosa account for 70% of all HAI GNB
infections in the US [123]. New antibiotics are
needed for the treatment of all ESBL-producing
Enterobacterales [1]
Klebsiella BLs (e.g. carbapenems) Carbapenem-resistance/third- VAP/HAP, BSI, UTI Commonly isolated in HAIs. Produces
pneumoniae generation cephalosporin- broad-spectrum β -lactamases that are active
resistance: critical threat against cefotaxime and ceftazidime [125,126]
Enterobacter spp. BLs (e.g. carbapenems, Carbapenem-resistance/third- BSI, GI, UTI, RTI Most commonly isolated Enterobacter spp. in HAIs
second-generation generation are E. aerogenes and E. cloacae. Highly motile.
cephalosporins, monobactams, cephalosporin-resistance: Plasmid-encoded resistance. Resistance arises from
carbapenems) critical threat efflux pump, enzyme secretion and low membrane
permeability [127]
Shigella spp. Fluoroquinolones, Fluoroquinolone-resistance: GI infection, BSI Particularly associated with gastroenteritis and
third-generation medium threat associated with large-scale morbidity and mortality
cephalosporins, azithromycin in low- and middle-income countries. Increasing
multidrug resistance is a serious concern [128,129]
Salmonella spp. Fluoroquinolones Fluoroquinolone-resistance: GI infection, BSI As with Shigella spp., Salmonella spp. (Typhi and
(ciprofloxacin) high threat non-Typhi) are associated with life-threatening GI
BLs (e.g. ampicillin, infections. Multidrug resistance is a serious
ceftriaxone), azithromycin, concern and new antibiotics are needed to tackle
tetracyclines, sulfonamide this threat [130–133]
Proteus spp. Third-generation - GI infections, Swarming bacterial species responsible for UTI.
cephalosporins carbapenems, pyelonephritis, MDR strains are becoming a problem [134–136].
polymyxins, BLs (e.g. UTI
mecillinam and pivmecillinam),
aminoglycosides,
nitrofurantoin, tigecycline,
colistin
Serratia BLs, tetracyclines - BSI, UTI, wound Environmental opportunistic pathogen causing
marcescens increasing numbers of HAIs, particularly in ICUs
[137,138]
Microaerophiles
Helicobacter spp. Clarithromycin, metronidazole Clarithromycin-resistance: high GI inflammation Antibiotic resistance among Helicobacter spp. has
threat (peptic ulcer) been described as having ‘reached alarming levels
worldwide affecting the efficacy of treatment’ [139]
Campylobacter Fluoroquinolones, BLs, Fluoroquinolone-resistance: GI infection Foodborne pathogen that has developed resistance
spp. aminoglycosides, macrolides, high threat (gastroenteritis) to multiple antibiotics, including high-level
tetracyclines, phenicols, fluoroquinolone resistance [140]
fosfomycin
Other Gram-negative bacteria
Haemophilus BLs, third-generation Ampicillin-resistance: medium RTI, BSI, Opportunistic pathogen, notable cause of fatal
influenzae cephalosporins, threat neurological infections in children, particularly among infants
chloramphenicol infections and children. Strains resistant to amoxicillin–
(meningitis) clavulanate, cefotaxime, and cefuroxime more
likely to be isolated from ICUs [141]
Neisseria BLs, third-generation Third-generation STI Common STI pathogen worldwide. The appearance
gonorrhoeae cephalosporins, cephalosporins/ of antibiotic resistance is a significant threat to
fluoroquinolones, macrolides fluoroquinolones: high threat health. Strains that are multi-resistant to
extended-spectrum cephalosporins and
azithromycin are especially dangerous [142]
BL, β -lactam; BSI, bloodstream infection; CF, cystic fibrosis; GI, gastrointestinal; GNB, Gram-negative bacteria/bacterial; HAI, healthcare-associated infection; HAP, hospital-
acquired [bacterial] pneumonia; IAI, intra-abdominal infection; ICU, intensive care unit; MDR, multidrug-resistant; RTI, respiratory tract infection; STI, sexually transmitted
infection; UTI, urinary tract infection; VAP, ventilator-acquired [bacterial] pneumonia.
Source: WHO 2017 [2]; Morris and Cerceo 2020 [119].

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S.S. Kanj, M. Bassetti, P. Kiratisin et al. International Journal of Antimicrobial Agents 60 (2022) 106633

to 2017, most of which were community acquired, although where > 500 patients had CDC-defined CRKP, 83% were carbapen-
healthcare-associated infections (HAI) are also a major source of emase producers and 94% of these expressed KPC [70].
these infections [60]. The ESBL-producing Enterobacterales are a The site of infection and knowledge of carbapenemase pro-
serious threat due to their resistance to many extended-spectrum duction are important, as these factors will guide treatment de-
penicillins and other agents, including cephalosporins and aztre- cisions [54]. Similar to infections with other MDR pathogens, poor
onam. Furthermore, they often have additional genes conferring re- source control and failure to implement early rapid diagnostics can
sistance to a wider range of antibiotics, including quinolones. ESBLs delay proper management(manuscript submitted for publication).
are produced across the Enterobacterales, and high rates of these The lack of availability of new drugs such as the newer BL–BLI
enzymes have been reported in E. coli, K. pneumoniae, K. oxytoca agents, plazomycin, cefiderocol and eravacycline, in some countries
and Proteus mirabilis [61,62]. The CTX-M ESBL inactivates a wide may hinder adequate treatment and force clinicians to use alterna-
range of antibiotics, including cefotaxime and ceftriaxone, and over tive drugs with lower efficacy and higher toxicity.
time has become more active against CAZ [63]. Bacteria producing Whenever bacterial pathogens are susceptible, preferable treat-
this enzyme are rapidly spreading worldwide and this is the most ments for CRE infections such as cystitis are ciprofloxacin,
frequently reported ESBL in the US [61]. This type of ESBL is dis- levofloxacin, trimethoprim–sulfamethoxazole, nitrofurantoin, fos-
tinct from β -lactamases such as TEM and SHV, which have a nar- fomycin or a single dose of an aminoglycoside [54]. Alternatively,
rower range of action [64,65]. CZA, MVB or cefiderocol can be used. For pyelonephritis or cUTI,
The MERINO trial did not support the use of piperacillin– preferred treatments are CZA, MVB, I–R, or cefiderocol, or, alterna-
tazobactam vs. meropenem in K. pneumoniae or E. coli BSIs with tively, aminoglycosides [54].
ceftriaxone resistance [66]. Following these results, carbapenems For non-UTI infections or where KPC has been identified, pre-
were considered the standard of care for the treatment of bac- ferred treatment options are CZA, MVB and I–R. Cefiderocol (for
teraemia with ESBL-producing Enterobacterales infections. How- indications other than BSI) and eravacycline or tigecycline (for non-
ever, this is controversial as there is a counter argument that car- bacteraemic intra-abdominal infection [IAI] only or in combination)
bapenems are not necessary for all patients with infections caused are alternative options, depending on the resistance profile of the
by ceftriaxone-resistant Enterobacterales, and that BL–BLIs can be pathogen (notably resistance to ertapenem or meropenem) [54]. In
used in appropriate settings [67]. This challenge is based on a re- cases in which an MBL is detected, the preferred treatment op-
port that some of the MICs in the MERINO trial may have been tions are CZA plus aztreonam or cefiderocol [54]. In cases where an
incorrectly determined by local laboratories who used MIC strip OXA-48-like carbapenemase has been detected, the preferred treat-
tests, and the observation that piperacillin–tazobactam was not ad- ment is CZA, or alternatively cefiderocol (for indications other than
ministered as an extended infusion [67,68]. Isolates from patients BSI), tigecycline or eravacycline (for cIAI only). Combination thera-
with worse outcomes were frequently found to be non-susceptible pies such as a β -lactam with an aminoglycoside, fluoroquinolone
to piperacillin–tazobactam when MICs were determined using ref- or polymyxin are not recommended for treating CRE infections if
erence methods [67]. Alternative new drugs and combinations with the pathogen is susceptible to a β -lactam [54].
in vitro activity against ESBL-producing Enterobacterales include: For cystitis caused by CRE that are resistant to ertapenem but
CZA, C/T, I–R, MVB, cefiderocol and plazomicin [50,59]. susceptible to meropenem, without available carbapenemase test-
ing, a standard infusion of meropenem may work due to high
achievable concentrations in the urine [54]. In cases of cystitis
4.2. Carbapenem-resistant Enterobacterales caused by CRE that are resistant to meropenem and other agents
such as aminoglycosides, including amikacin and plazomicin, al-
The CREs are a more serious threat than ESBLs; they account ternative options include CZA, MVB, I–R and cefiderocol [54]. For
for > 13 0 0 0 nosocomial infections and > 10 0 0 deaths per year isolates producing MBLs (NDM, IMP or VIM), CZA plus aztreonam,
in the US [54]. Carbapenemase-producing isolates are the cause of aztreonam–avibactam or cefiderocol are preferred [53,79]. Colistin
ca. 50% of all CRE infections in the US [69,70]. There is hetero- (not polymyxin B), notwithstanding the side effects, is also an al-
geneity within the CRE, with differing sets of carbapenemases be- ternative, although not preferred [54,80].
ing produced, and consequently there is resistance to various car- Complicated UTI and pyelonephritis caused by CRKP that is re-
bapenem antibiotics. The most common of the Ambler classes A, sistant to both ertapenem or meropenem are best treated with
B and D enzymes are KPCs of the class A type, and these can be CZA, MVB, I–R or cefiderocol [54]. Oral fosfomycin should be
produced by any of the species belonging to the Enterobacterales. avoided [81,82]. For infections outside the urinary tract caused
In the US, the most prominent type of carbapenemases are KPCs; by K. pneumoniae that are resistant to both ertapenem and
other types such as class B MBLs (e.g. NDM, VIM, IMP) and class meropenem, it is important to identify the specific carbapenemase
D oxacillinase (e.g. OXA-48-like) are much less frequently reported gene to give specific treatment [75,83].
[71,72]. It should be noted that carbapenem resistance not only For KPC producers, the preferred options are CZA, MVB and I–R,
arises from carbapenemase production but also decreased porin with cefiderocol as an alternative [81]. For IAIs, depending on the
expression and increased efflux pump action [73,74]. severity of the infection, tigecycline is an alternative treatment but
Carbapenem-resistant K. pneumoniae are the most common and can be limited by gastrointestinal side effects, particularly when
clinically important of the CRE reported worldwide [75]. The geo- high doses are used; eravacycline is a newer alternative but data
graphic variation of the carbapenem resistance genes varies across are limited for this monotherapy [54,81,84]. For isolates producing
continents [75]. When comparing studies, it is important to note MBLs, such as NDM, IMP or VIM, the preferred drugs are CZA with
that phenotypic definitions of carbapenem-resistant K. pneumoniae aztreonam or cefiderocol alone [54]. For Enterobacterales produc-
(CRKP) may differ. In South-East Asia, NDM and other MBLs (e.g. ing OXA-48-like carbapenemases, CZA is preferred [54].
IMP, VIM) and OXA-48–type are predominant carbapenemases in
CRE [76]. In the European Survey on carbapenemase-producing 4.3. Carbapenem-resistant Acinetobacter baumannii
Enterobacteriaceae (EuSCAPE), 37% of the tested CRKP had a car-
bapenemase gene: KPC (42%) and OXA-48 (38%) were predomi- Acinetobacter baumannii is found in many healthcare environ-
nantly encoded [77]. In the US, the CDC Gram-negative initiative ments and is a highly effective human coloniser in hospitals [85].
surveillance revealed that 47.9% of tested CRE isolates were KPC- Acinetobacter baumannii can easily survive on multiple surfaces,
producing species [78]. In another study from the US (CRACKLE-2), causing hospital infections and leading to numerous global out-

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S.S. Kanj, M. Bassetti, P. Kiratisin et al. International Journal of Antimicrobial Agents 60 (2022) 106633

breaks [86,87]. Furthermore, there have been reports of CRAB An analysis of seven studies (total = 1613 patients) found that
strains being transmitted from countries with high antimicrobial patients with CRPA BSIs were at higher risk of death than non-
resistance rates to countries where the rates are usually low, such CRPA BSIs (pooled ORs, 3.07 and 1.46) [102] and showed that 8–
as from Spain to Norway [87]. Infections due to A. baumannii are 18.4% of deaths in this study were attributable to carbapenem re-
frequently found in intensive care units (ICUs), where they are im- sistance. Risk factors for CRPA infection include carbapenem use,
plicated as the cause of VAP, UTIs and bacteraemia [88]. The preva- other antibiotic use [103,104] such as fluoroquinolones, medical
lence of A. baumannii infection and colonisation is higher in ICUs devices and ICU admission [105]. Additionally, a study in Japan
since patients with severe clinical conditions are often hospitalised showed a clear correlation between carbapenem consumption and
in these facilities. the prevalence of CRPA on a national scale [95].
Antibiotic resistance in A. baumannii is frequently due to low Alternative treatments to carbapenems include antipseu-
outer membrane permeability, antibiotic binding-site modifications domonal drugs (e.g. antipseudomonal cephalosporins such as
and efflux pump expression [89,90]. The acquisition of carbapene- CAZ, cefepime and piperacillin–tazobactam) and are usually part-
mases is also an important mechanism of resistance for CRAB and nered with another active agent such as an aminoglycoside (e.g.
resistance genes can also be gained through the acquisition of mo- amikacin) [103]. Carbapenems should be reserved for polymicro-
bile genetic elements [89,91]. bial infections or P. aeruginosa isolates that are resistant to other
Various antimicrobials are used against CRAB, including β -lactams [106]. Resistance to antipseudomonal drugs is increasing
polymyxins (such as polymyxins B or E [colistin]), tetracyclines and MDR P. aeruginosa showing resistance to three or more drug
(such as tigecycline and minocycline), β -lactams in combination classes has emerged and spread across different regions worldwide
with β -lactamase inhibitors (such as sulbactam) and other com- [107].
binations such as trimethoprim–sulfamethoxazole. However, many The C/T combination is one of the preferred treatment op-
A. baumannii strains show high-level resistance to these agents tions for MDR/XDR Pseudomonas infections [108]. In an analysis of
and there are pharmacokinetic limitations with polymyxins and 11 clinical studies (number of strains ranged from 38 to 3229),
tetracyclines: high and potentially toxic doses are necessary to the susceptibility of MDR/XDR P. aeruginosa to C/T ranged from
achieve good tissue levels [92]. However, the newer tetracycline, 55–96.6% [108]. When compared with other agents, C/T had a
eravacycline, shows efficacy against CRAB infections with low MIC lower probability of co-resistance in β -lactam-resistant P. aerugi-
values. This drug was shown to be non-inferior to ertapenem nosa [48]; however, dosing and infusion need to be optimised ac-
and meropenem against CRAB in two randomised clinical trials cording to indication. Other notable effective approaches to treat-
but is only approved for use for cIAI. However, in two further ing CRPA infections include cefiderocol, CZA and I–R [81].
Phase III clinical trials, eravacycline was inferior to levofloxacin
and ertapenem in the treatment of cUTI [92,93]. Cefiderocol has 5. Real-world evidence
shown efficacy in CRAB infections and non-inferiority to IPM in the
treatment of cUTIs has been demonstrated [19,92]. Although it is Various observational studies have added to the body of clin-
now approved for the treatment of cUTIs, the CREDIBLE-CR study ical trial evidence showing the viability of using monotherapies
(where patients with pneumonia, sepsis and UTI participated, and and antibiotic combinations to treat MDR-GNB infections in reg-
where CRAB isolates were identified in 46% of patients) all-cause ular clinical practice. A recent study involving 22 clinical centres
mortality at the end of the study was higher when using cefidero- from Italy (n = 577) showed that CZA is an effective option for
col (50%) compared with BAT (18%) in patients with Acinetobacter treating KPC infections (e.g. BSIs and UTIs) when used alone [109].
spp. positive cultures [53]. More investigations are needed to support its use in lower respi-
The OXA (class D) are the most prevalent types of carbapene- ratory tract infections and the potential benefits of longer infusion
mases among A. baumannii isolates worldwide. Among these are times [109]. A retrospective cohort study (n = 203) found that CZA
six subclasses: OXA-51-like, OXA-23-like, OXA-24/40-like, OXA-58- did not impact clinical failure in the overall population, or high-
like, OXA-143-like and OXA-235-like [94]. To address such resistant risk subgroups or 30-day mortality among those with CRE or Pseu-
infections, new approaches are being developed for treating re- domonas spp. infections [110]. However, receipt of CZA within 48
sistant A. baumannii infections, including new β -lactam inhibitors hours of infection onset was associated with improved clinical out-
in combination with existing β -lactams and non-β -lactams, new comes [110]. It was concluded that CZA can be an effective ther-
polymyxins, a new aminoglycoside (apramycin), monoclonal anti- apy for CRE and MDR Pseudomonas, but that there is a need for
body treatments and bacteriophages [93]. advances in the treatment of vulnerable patients with pneumonia
and severe renal impairment.
Real-world studies and observational studies have shown the
4.4. Carbapenem-resistant Pseudomonas aeruginosa efficacy and safety of C/T in a range of different MDR/XDR P. aerug-
inosa infections, including UTI, IAI, HAP, VAP and skin/soft tissue
Pseudomonas aeruginosa is increasingly associated with nosoco- infections [42,108,111–113]. The C/T combination has also shown
mial infections, particularly in immunocompromised patients and lower toxicity than BATs such as polymyxin or aminoglycosides in
those with indwelling devices [95]. Carbapenem-resistant P. aerug- the treatment of P. aeruginosa infections [114].
inosa is associated with a high risk of mortality. Worldwide, MBLs Although the body of real-world evidence is growing, more of
are the most prevalent type of carbapenemase produced by clin- these studies are needed to determine the value of new antibi-
ical isolates of CRPA; VIM MBLs are the most widely dissemi- otic combinations in everyday use in critically ill patients, and to
nated, followed by imipenemases [96]. In many territories, car- evaluate their usefulness compared with older treatment options
bapenem resistance is due to MBLs that diminish the usefulness such as polymyxins, tigecycline, fosfomycin and aminoglycosides
of β -lactamase inhibitors in the treatment of CRPA infections [97]. [20,115].
In the US, 10–20% of P. aeruginosa isolates are resistant to at least
one carbapenem, making this resistance a serious problem [98,99]. 6. Conclusions and final recommendation
Compared with worldwide literature, India reports increasing MBLs
(NDM and VIM) in addition to other resistance mechanisms, which Antimicrobial resistance in GNB is a global concern and signifi-
further compromise the efficacy of the newer BL–BLIs [100], whilst cantly affects outcomes in patients with limited options for treat-
KPC-producing P. aeruginosa is becoming a concern in China [101]. ment. To date, there is no single agent BL–BLI with a spectrum

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S.S. Kanj, M. Bassetti, P. Kiratisin et al. International Journal of Antimicrobial Agents 60 (2022) 106633

that covers all MDR-GNB in empiric or targeted therapy. Whilst ce- [6] Talbot GH, Jezek A, Murray BE, Jones RN, Ebright RH, Nau GJ, et al. The In-
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tract infections or complicated intra-abdominal infections (REPRISE):
outside the submitted work. All authors received an honorarium
a randomised, pathogen-directed, phase 3 study. Lancet Infect Dis
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