Drugs (2024) 84:1519–1539

https://doi.org/10.1007/s40265-024-02102-8

REVIEW ARTICLE

The Challenge of Treating Infections Caused by Metallo‐β‐

Lactamase–Producing Gram‑Negative Bacteria: A Narrative Review
Carmen Hidalgo‑Tenorio1,10 · German Bou2,9 · Antonio Oliver3,9 · Montserrat Rodríguez‑Aguirregabiria4 ·
Miguel Salavert5 · Luis Martínez‑Martínez6,7,8,9

Accepted: 19 September 2024 / Published online: 28 October 2024

© The Author(s) 2024

Abstract
Gram-negative multidrug-resistant (MDR) bacteria, including Enterobacterales, Acinetobacter baumannii, and Pseudomonas
aeruginosa, pose a significant challenge in clinical practice. Infections caused by metallo-β-lactamase (MBL)–producing
Gram-negative organisms, in particular, require careful consideration due to their complexity and varied prevalence, given
that the microbiological diagnosis of these pathogens is intricate and compounded by challenges in assessing the efficacy
of anti-MBL antimicrobials. We discuss both established and new approaches in the treatment of MBL–producing Gram-
negative infections, focusing on 3 strategies: colistin; the recently approved combination of aztreonam with avibactam (or
with ceftazidime/avibactam); and cefiderocol. Despite its significant activity against various Gram-negative pathogens, the
efficacy of colistin is limited by resistance mechanisms, while nephrotoxicity and acute renal injury call for careful dosing
and monitoring in clinical practice. Aztreonam combined with avibactam (or with avibactam/ceftazidime if aztreonam
plus avibactam is not available) exhibits potent activity against MBL–producing Gram-negative pathogens. Cefiderocol in
monotherapy is effective against a wide range of multidrug-resistant organisms, including MBL producers, and favorable
clinical outcomes have been observed in various clinical trials and case series. After examining scientific evidence in the
management of infections caused by MBL–producing Gram-negative bacteria, we have developed a comprehensive clinical
algorithm to guide therapeutic decision making. We recommend reserving colistin as a last-resort option for MDR Gram-
negative infections. Cefiderocol and aztreonam/avibactam represent favorable options against MBL–producing pathogens.
In the case of P. aeruginosa with MBL–producing enzymes and with difficult-to-treat resistance, cefiderocol is the preferred
option. Further research is needed to optimize treatment strategies and minimize resistance.

multidisciplinary team to design a strategy for prevention,

1 Introduction
diagnosis and treatment [2]. The target patient is usually a
complex case involving multiple comorbidities, prolonged
Antimicrobial resistance (AMR) is recognized as one of
hospitalization, and bacterial colonization [3, 4]. Mortality is
the major global health challenges of the 21st century. The
influenced by host factors, infection-related factors, and ther-
global burden associated with drug-resistant infections
apeutic factors, such as delay in initiating antibiotic therapy
assessed in 2019 was an estimated 4.95 million deaths, of
[5]. Holistic treatment includes supportive therapy, when
which 25.6% were directly attributable to drug resistance.
necessary, control of the infectious focus whenever possible,
Actions for reducing AMR burden include therapeutic
and timely and appropriate antimicrobial administration [6].
approaches, the reduction of antimicrobial selective pres-
Local epidemiology and microorganism susceptibility must
sure, the reduction of transmission, and the restoration of
also be considered [7].
populations of antibiotic-susceptible bacteria [1]. The man-
In 2017, the World Health Organization published a list
agement of infections caused by multidrug-resistant micro-
of antibiotic-resistant “priority pathogens” [8], recognizing
organisms should be approached from a global institutional
carbapenem-resistant Enterobacterales, Pseudomonas aer-
perspective and requires the collaboration of an expert
uginosa and Acinetobacter spp. as bacteria of critical impor-
tance [8]. The list was updated in 2024 [9] and in this new
version, carbapenem-resistant P. aeruginosa is not included
Extended author information available on the last page of the article

Vol.:(0123456789)
1520 C. Hidalgo‑Tenorio et al.

2 Mechanism and Type

Key Points of Metallo‑β‑Lactamases (MBLs)
Metallo-β-lactamase (MBL)-producing Gram-negative The biochemical mechanism of β-lactam hydrolysis by
organisms, such as Enterobacterales, Acinetobacter MBLs proposes that the active site orients and focuses the
baumannii, and Pseudomonas aeruginosa, present a β-lactam bond to make a more straightforward nucleophilic
complex and varied prevalence in clinical practice, with attack by zinc. The most frequent zinc-binding motif is his-
intricate microbiological diagnosis and challenges in tidine-X-histidine-X-aspartic acid (HXHXD).
assessing the efficacy of anti-MBL antimicrobials. Metallo-β-lactamases are encoded by chromosomal
Cefiderocol and the recent combination of aztreonam or plasmid genes. Most bacteria producing chromosomal
with avibactam (or with ceftazidime/avibactam if MBLs are environmental organisms or opportunistic patho-
aztreonam/avibactam are not available) are identified as gens that usually do not cause severe infections, the most
favorable treatment options for MBL–producing Gram- clinically relevant being Stenotrophomonas maltophilia
negative infections, while colistin, despite its in vitro (producing the L1 enzyme) and Bacillus anthracis (produc-
activity, is limited by difficulties for in vitro testing, the ing Bla2). Regarding plasmid-mediated MBLs, the most
selection of resistance mechanisms and nephrotoxicity, frequent families include imipenemase (IMP; active on imi-
making it a last-resort option. penem), VIM (Verona integron-encoded MBL), and NDM
(New Delhi MBL), but many other less common enzymes
A comprehensive clinical algorithm recommends cefi- are also known [11–13]. On most occasions, MBL plasmid
derocol as the preferred option for P. aeruginosa with genes are located within a variety of integrons (mainly class
difficult-to-treat resistance. Cefiderocol and aztreonam/ 1 integrons).
avibactam are highlighted as a favorable options for Metallo-β-lactamases are divided into three subclasses
MBL–producing Enterobacterales. Continuous research (B1, B2, and B3) based on their amino acid sequence at
is emphasized to optimize treatment strategies and mini- the active site, zinc ligands and stoichiometry, loop archi-
mize resistance development. tecture and substrate profiles [11–13]. In the B1 group,
key zinc is coordinating residues of three histidines and
one cysteine. This group include VIM, IMP, NDM plas-
mid-mediated enzymes and most of the chromosomally
encoded MBLs. Class B2 includes enzymes that harbor an
asparagine instead of the histidine at the first position of
the principal zinc-binding motif, NXHXD. They accom-
in the “critical” group, but is included in the “high prior- modate a single zinc ion (despite that most MBLs accom-
ity” group. In most regions, carbapenem resistance in these modate two zinc ions) and include the CphA enzyme from
organisms is frequently due to production of carbapenem- Aeromonas spp. Finally, the class B3, which is function-
hydrolyzing β-lactamases (carbapenemases), which include ally represented as a tetramer, includes the already-men-
enzymes belonging to molecular classes A (i.e., Klebsiella tioned L1 enzyme.
pneumoniae carbapenemase [KPC] enzymes), B (metallo-β-
lactamases [MBLs]), C (only a few examples known, such as
CMY-10) or D (OXA-like enzymes), that fall into functional 3 Testing MBL‑Producing Bacteria:
groups 2df, 2f, or 3 (Table 1). In some countries and for Challenges and Limitations
some organisms (i.e., P. aeruginosa or Enterobacter cloa-
cae complex in Spain), carbapenem resistance is more com- Because MBL–producing bacteria usually express other
monly associated with a combination of the production of resistance mechanisms, their susceptibility is not predict-
β-lactamases that have poor anti-carbapenem activity, porin able and, in practice, an antibiogram is needed for inform-
loss, and upregulated efflux pumps. ing optimally directed treatment.
Bush et al provide a comprehensive overview of carbap- Metallo-β-lactamase–producing organisms are suscep-
enemases and other important β-lactamases [10]. The most tible to aztreonam (ATM) when no additional enzymes
important discoveries on β-lactamases, and MBL in particu- hydrolyzing this compound are also expressed. A high pro-
lar, are presented in Table 2. portion of isolates expressing MBL are also susceptible
This paper will review the most relevant epidemiologic to cefiderocol [14, 15]. When an MBL enzyme is poorly
and microbiological aspects and the main therapeutic options expressed in Enterobacterales, the organism can present
for infections caused by MBL–producing microorganisms. some level of susceptibility to carbapenems.
Metallo-β-Lactamase Treatment 1521

Table 1  Classification of β-lactamases of major clinical relevance (Bush and Jacoby 2010 [164], Bush and Bradford 2020 [10])
Molecular Type Functional Relevant/distinc- Inhibition by Inhibition by Inhibition Examples (families or representatives)
class group tive substrates clavulanic acid avibactam by EDTA

A SBL 2a P + + − PC1
2b P, Cp + + − TEM-1, SHV-1
2be P, Cp, E, M + + − TEM-ESBL, SHV-ESBL, CTX-M
2br P − + − Inhibitor-resistant TEM, SHV-10
2c P ± + − CARB-1
2e P, Cp, E + + − CepA
2f P, Cp, E, M, Cp ± + − KPC, SME
B MBL 3a (B1) P, Cp, E, Cb − − + IMP, VIM, NMD
3a (B3) L1
3b (B2) Cb − − + CphA
C SBL 1 Cp − + − Chromosomal AmpC
Plasmid-mediated AmpC
1e Cp, E − + − GC1
D SBL 2d P ± + − OXA-1
2de P, E, M ± + − OXA-11
2df P, Cb − + − OXA-48, OXA-23

Cb carbapenems, Cp cephalosporins, E expanded-spectrum β-lactamases, ESBL extended-spectrum β-lactamases, M monobactams, MBLs

metallo-β-lactamases, P penicillins, SBL serine β-lactamases

Table 2  Milestones in β-lactamase discovery with emphasis on metallo-β-lactamases (MBLs)

Year Milestone Comments Refs.

1966 Essential role of zinc on the activity of the Bacillus cereus “cepha- The enzyme was inhibited by ethylenediaminetet- [154]
losporinase” raacetic acid (EDTA)
1980 Definition of structural (molecular) classes of β-lactamases Class A (serine β-lactamases, or SBL); Class B: MBLs [155]
1985 Introduction of terms MBLs and metalloenzymes MBLs hydrolyze carbapenems (carbapenemases) [156]
1981 Class C and class D SBL defined [157, 158]
1988
1988 First functional classification of β-lactamases Classification based on substrate and inhibitor (clavu- [159]
lanic acid vs EDTA) profiles
1991 The first acquired MBL (IMP-1) identified (in Pseudomonas aer- [160]
uginosa, in Japan)
1995 Updated functional classification of β-lactamases Functional groups 1, 2 and 3 defined [161]
1999 VIM-1 discovered (in P. aeruginosa, in Italy) [162]
2008 NDM-1 discovered (in Klebsiella pneumoniae and Escherichia coli, [163]
in a traveler from India to Sweden)
2010 Updated functional classification of β-lactamases Additional β-lactamase subgroups defined [164]

Phenotypic tests for MBL detection are based on the (usually) meropenem is incubated into a bacterial suspen-
hydrolytic activity of these enzymes against carbapenems sion; the disk is then placed on the surface of a plate,
(and other β-lactams). For MBL producers, minimum which has been previously streaked with a carbapenem-
inhibitory concentrations (MICs) of carbapenems will be susceptible E. coli marker strain; after incubation, a reduc-
reduced in the presence of an efficient MBL inhibitor (i.e., tion in the size of the inhibition zone indicates that the
Ethylenediaminetetraacetic acid [EDTA], dipicolinic acid, investigated bacteria produce a carbapenemase. When con-
sodium mercaptoacetate, 1,10-O-phenanthroline), but this sidering P. aeruginosa and Acinetobacter baumannii, both
approach is not commonly used in the clinical laboratory. sensitivity and specificity improve when bacterial cells are
In the carbapenem inactivation method (CIM), a disk of extracted with 0.5 M TrisHCl (CIMTris). Another variant,
1522 C. Hidalgo‑Tenorio et al.

EDTA-mCIM (eCIM), can differentiate MBLs and SBL In vitro activity of cefiderocol can be alternatively determined
among carbapenemase producers [16–19]. by disk diffusion; EUCAST has defined areas of technical
The Carba NP assay is a rapid (less than 3 h) turna- uncertainty for this assay (ATU, available at EUCAST [36])
round test. It detects acidification of a solution containing for both Enterobacterales and P. aeruginosa, and when they
a carbapenem after the compound has been degraded by a occur, EUCAST has suggested several possible solutions
carbapenemase [20, 21]. (available at EUCAST [41]).
Peaks of hydrolyzed carbapenems can be detected by Results from susceptibility testing assays for MBL–pro-
matrix-assisted laser desorption/ionization time-of-flight ducing organisms should be presented as clinical catego-
(MALDI-Tof) [22, 23] (and by liquid chromatography- ries alone or with detailed MIC values (of great value
coupled tandem mass spectrometry (LC-MS/MS) [24]. from a clinical perspective when pharmacokinetics/phar-
Metallo-β-lactamases and other common carbapen- macodynamics [PK/PD] issues are considered in concrete
emases can be detected by multiplex lateral flow immu- patients), as defined by committees such as EUCAST or
noassays, which are technically simple, provide results Clinical and Laboratory Standards Institute (CLSI). Break-
within 15 min, and have good sensitivity and specificity. points for colistin, ATM/AVI and cefiderocol are presented
Unfortunately, these tests show negative results for some in Tables 3 (MIC values) and 4 (inhibition zones).
carbapenemase alleles [25].
Molecular tests are faster than methods based on bac-
terial growth. They can detect one or more genes coding 4 Epidemiology
for MBLs but require the genes to be previously known.
There are multiple commercial molecular assays based on The global prevalence and geographic distribution of
PCR, loop-mediated isothermal amplification (LAMP) MBLs are not comprehensively known due to scant data
and DNA microarrays that detect several MBLs with high and limited updated information, particularly in certain
sensitivity and specificity and can be applied directly to regions such as Africa.
clinical samples or positive blood culture bottles [26–29]. Verona integron-encoded MBL enzymes have been
More recently, whole-genome sequencing (WGS) has been reported worldwide from multiple species, particularly P.
increasingly used for the detection of resistance-related aeruginosa and Enterobacterales (mainly K. pneumoniae,
genes, including those coding for MBLs [30–33]. E coli and E. cloacae complex). These enzymes are widely
In addition, various testing methods are available for drugs distributed in Europe, and several outbreaks have been
targeting microorganisms producing MBLs, including colistin, reported in Greece, Italy, Spain, and other countries [42].
aztreonam plus avibactam (ATM/AVI) (or ATM plus ceftazi- New Delhi MBL variants are widespread in the Indian
dime [CAZ]/AVI) and cefiderocol. subcontinent. India, Pakistan and Bangladesh are consid-
For colistin, the reference method is broth microdilution. ered reservoirs for these enzymes, as is the Balkan region
Agar dilution, disk diffusion or gradient test, are not recom- in Europe. New Delhi MBL enzymes are the second most
mended, and semi-automated methods can produce false sus- frequent enzymes (after OXA-48) in the Middle East
ceptibility results. Aztreonam plus avibactam may be tested by [43, 44] and predominate in some regions of Russia [45].
standard methods in clinical laboratories. For ATM combined Outbreaks with NDM–producing organisms have been
with CAZ/AVI, in vitro synergy tests are not standardized and reported in several European countries including Italy,
the results from different methods for synergism may offer Greece, Romania, Poland, and Denmark [46]. An increas-
variable results [34–39]. ing number of NDM-1- and NDM-1/OXA-48–producing
For testing cefiderocol, MICs of cefiderocol in cation- Klebsiella pneumoniae were detected in Germany in 2022,
adjusted Mueller-Hinton broth are not reproducible and do associated with patients with a documented history of pre-
not represent the actual in vivo activity of this compound, vious presence in Ukraine [47].
which is highly influenced by iron content. Minimum inhibi- The IMPs are currently endemic in Japan and are more
tory concentrations of cefiderocol should be determined in an common in Asian countries [48, 49], with IMP-4 being
iron-depleted medium (≤ 0.03 mg/L of iron), which is not particularly important in China and Australia [50]. A large
usually available in routine clinical laboratories and is not cur- number of acquired minor MBLs limited to specific geo-
rently used by commercial panels of semi-automated methods graphical areas are also known; for a review, see reference
[40]. Several commercial tests based on broth microdilution [10].
are available as an easy approach to determining cefiderocol The EuSCAPE project analyzed carbapenemase pro-
MICs in clinical laboratories; the European Committee on duction in Enterobacteriaceae isolated from 38 European
Antimicrobial Susceptibility Testing (EUCAST) evaluation countries in 2015. The most common enzymes were KPC
of these assays is ongoing, but results are not yet available. and OXA-48 enzymes, but VIM was most common in
Metallo-β-Lactamase Treatment 1523

Hungary and NDM in Serbia and Montenegro. The IMPs

ATU​area of technical uncertainty, CLSI Clinical and Laboratory Standards Institute, EUCAST European Committee for Antimicrobial Susceptibility Testing, IE insufficient evidence, MIC mini-
CLSI

≥16
≥16
≥16
≥16
were rare in most countries [51].
Among Enterobacterales non-susceptible to meropenem
evaluated in the ATLAS global surveillance program iso-

EUCAST
Resistant
lated in 2018–2019, MBLs were more frequent (36.7%
of isolates) than KPCs (25.5%) or OXA-48-like (24.1%)

>2
>2
IE
IE
enzymes, and were particularly more frequent in Africa,
Middle East and the Asia/Pacific (APAC) region. Kleb-
Intermediate

siella pneumoniae represented 71.5% of the isolates. New

Delhi MBL enzymes represented the large majority of the
CLSI

identified MBLs (88.4% in total, with NDM-1 in 68.7%

8
8
8
8
of NDM–producing isolates). Verona integron-encoded
MBL and IMP enzymes were detected in 11.1% (VIM-1
CLSI

in 76.1% of the VIM-producing isolates) and 0.5%, respec-

≤4
≤4
≤4
≤4

tively [52, 53].

In another recent study on Enterobacterales from 64
Cefiderocol
Susceptible

medical centers in Europe, Latin-America and the Asia-

EUCAST

Pacific (APAC region resistant to the new beta-lactamase

≤2
≤2

inhibitor combinations, MBL genes were detected in

IE
IE

35.0% of carbapenem-resistant Enterobacterales (CRE),

Table 3  The MIC (mg/L) breakpoints for colistin, aztreonam/avibactam and cefiderocol against different microorganisms.

and the most frequent MBL was NDM (29.9%). The

EUCAST
Resistant

highest rates of MBL–producing organisms occurred in

Aztreonam/avibactam

APAC (59.5%), followed by Latin-America (34.0%) and

>4

Europe (23.6% and 28.9%, in Western and Eastern coun-

tries, respectively [54]. In the SMART study, MBLs were
Susceptible

detected in 4.3% of P. aeruginosa from the APAC region

EUCAST

(2017–2020), although rates as high as 32.3% and 10.7%

were observed in isolates from Vietnam and Thailand,
≤4

respectively [55]. Also, in the SMART study considering

P. aeruginosa isolates from Latin America in the period
CLSI

CLSI breakpoints for Enterobacterales do not apply to Salmonella and Shigella spp.

2018–2020, MBLs were identified in 7.6% of isolates, with

≥4
≥4
≥4

Breakpoints in brackets (details in: https://​eucast.​org/​eucas​tguid​anced​ocume​nts)

rates of 25.3%, 10.6%, and 8.6% in isolates from Chile,

Colombia, and Mexico, respectively [56].
EUCAST
Resistant

The CARBA-ES-19 study, conducted in 71 hospi-

>(2)b
>(4)b
>(2)b

tals, found that the most frequent carbapenemases in K.

pneumoniae and E. coli were OXA-48 and KPC [57]. In
the retrospective CARBA-MAP study (2014 to 2018, 30
hospitals), which focussed on carbapenemase-producing
CLSI

≤2
≤2
≤2

Enterobacterales and P. aeruginosa, VIM, NDM and OXA-

Empty cells when breakpoints have not been defined

48-like+NDM MBLs were found in 6.9%, 1.8% and 1.3%

Susceptible

K. pneumoniae, respectively. In the E. cloacae complex (n

EUCAST
Colistin

= 334), class B enzymes were the most frequent carbapen-

≤ (2)b
≤ (4)b
≤ (2)b

emases (VIM, 37.4%; NDM, 19.2% and IMP 3.3%). E. coli

(n = 114) and K. aerogenes (n = 11) produced VIM enzymes
in 14.9% and 36.3%, while NDM was expressed by 6.1% and
Stenotrophomonas maltophilia

mum inhibitory concentration

9.1% of these species, respectively [58].

Pseudomonas aeruginosa

Most carbapenem-resistant P. aeruginosa strains in Spain

do not produce carbapenemases. However, when they are
Acinetobacter spp.

expressed, the most commonplace enzymes are of the VIM

Enterobacteralesa

type. In a multicenter study with isolates from 2022, a slight

decrease in VIM enzymes was observed in comparison to
a previous similar study in 2017, although carbapenemases
b
a
1524 C. Hidalgo‑Tenorio et al.

Table 4  Inhibition zone (mm) breakpoints for colistin, aztreonam-avibactam (30–20 µg disc) and cefiderocol (30 µg disc) against different
groups of microorganisms
Aztreonam/avibactam Cefiderocol
Susceptible ATU​ Resistant Susceptible ATU​ Intermediate Resistant
EUCAST EUCAST EUCAST CLSI EUCAST CLSI EUCAST CLSI

Enterobacterales ≥25 22–24 <25 ≥23 ≥16 21–23 9–15 <23 ≤8

Pseudomonas aeruginosa ≥22 ≥18 21–22 13–17 <22 ≤12
Acinetobacter spp. Notea ≥15b
Stenotrophomonas maltophilia Notec ≥15

Breakpoints not defined by EUCAST or CLSI for colistin

ATU​area of technical uncertainty, CLSI Clinical and Laboratory Standards Institute, EUCAST European Committee for Antimicrobial Suscepti-
bility Testing, MIC minimum inhibitory concentration
a
Zone diameters of ≥17 mm correspond to MIC values ≤2 mg/L
b
Zone diameters ≤ 14 mm should not be interpreted or reported because zone diameters ≤ 14 mm occur with resistant, intermediate, and suscep-
tible isolates. A MIC test should be done in this situation
c
Zone diameters of ≥20 mm corresponds to MIC values ≤2 mg/L

significantly increased in extensively drug-resistant or mero- mutations in lipid A biosynthesis genes lpxA, lpxC, or lpxD,
penem-resistant isolates [59]. leading to complete loss of LPS production [64]. Several
mobile colistin resistance (mcr) genes carried by transfer-
able plasmids have been reported, after they were discovered
5 Drugs for Treating Infections Caused (2016) in an E. coli strain isolated in China [65].
by MBL–Producing Organisms An extensive global surveillance program from 39 coun-
tries has noted an association between the presence of a
From a clinical perspective, it is standard practice for clini- carbapenemase and increased resistance to colistin among
cians to directly receive microbiological laboratory results surveillance isolates of Enterobacteriaceae. Colistin suscep-
in a report. These reports are interpreted by microbiologists tibility was established at 98.4% overall, while it decreased
based on in vitro findings. to 88% among carbapenemase producers. Colistin suscep-
Furthermore, the selection of treatment must carefully tibility was 92.6% among MBL-positive isolates [66]. In a
consider various additional factors. These include the sever- large surveillance study (SIDERO-CR), which included 457
ity of the infection, the patient’s comorbidities, the antibi- isolated carbapenem-resistant Enterobacteriaceae, colistin
otic penetration into the site of infection, and any potential susceptibility was 93.5% for VIM producers and 78.4% for
adverse effects. Each of these factors is critical in deter- NDM producers [67]. In an observational prospective study
mining the appropriateness and efficacy of the treatment performed in two Italian hospitals, which focused on MBL,
regimen. NMD-producing strains had a colistin susceptibility rate of
90.2%, while VIM-producing strains had a rate of 80% [68].
5.1 Colistin Although colistin and polymyxin B were initially aban-
doned due to toxicity, they regained relevance given the lack
Colistin (polymyxin E) shows significant activity against of effective antimicrobials against MDR Gram-negative
most Enterobacterales, A. baumannii, P. aeruginosa and pathogens [69, 70].
S. maltophilia. However, some Gram-negative species are There are other issues that clearly limit their use in clini-
naturally resistant to colistin, including Proteus spp., Provi- cal practice. First, PK/PD is critical for optimizing dosing.
dencia spp., Morganella morganii, or S. marcescens. Colistin administration as an inactive prodrug affects the
The most common colistin resistance mechanism is the time needed to achieve desirable plasma concentrations
modification of lipopolysaccharides (LPS) via the addition [71]. A target plasma colistin concentration of 2 mg/L seems
of cationic molecules, such as L-aminoarabinose and phos- appropriate, but the risk of nephrotoxicity increases above
phoethanolamine [60]. This is frequently linked to muta- 2.5 mg/L. Achieving target concentrations in plasma may not
tions in 2-component regulatory systems [61, 62]. Mutations be sufficient for adequately treating lower respiratory tract
in mgrB, coding for a negative PhoPQ regulator, are fre- infections due to reduced lung penetration [71–74].
quently associated with colistin resistance in K. pneumoniae Preclinical lung infection models suggest poor in vivo
[63]. Colistin resistance in A. baumannii may emerge by response to the polymyxins when administered parenterally
Metallo-β-Lactamase Treatment 1525

[74]. The PK and concentration of colistin in bronchoalveo- Enterobacterales tested were inhibited at a concentration
lar lavage (BAL) were evaluated in 13 adult patients who threshold of 8 mg/L [84].
developed ventilator-associated pneumonia (VAP) caused Resistance to ATM/AVI in MBL producing Enterobac-
by A. baumannii and P. aeruginosa during their ICU stay. terales has been reported to be lower than 1% globally [85].
The administration of 2 million International Units (IU) of However, resistance to ATM/AVI in 15% NDM producing E.
colistin every 8 h results in apparently suboptimal plasma coli has been specifically linked to the production of CMY-
concentrations of colistin, which was undetectable in BAL 42 and/or PBP3 modifications [86]. Production of double
[75]. Epithelial lining fluid penetration ratios appear reduced carbapenemases may also compromise the activity of ATM/
in critically ill patients; nebulized administration of antibiot- AVI in Enterobacterales [87]. The picture is different for P.
ics has been advocated to achieve target concentrations at the aeruginosa. First, the co-production of MBLs and ESBL
infection site with minimal systemic toxicity [76]. The data or other carbapenemases is infrequent in this species. Sec-
indicate that higher doses of nebulized colistin may achieve ond, while the overexpression of AmpC may compromise
adequate concentrations in lung compartments; however, the activity of ATM to some extent, the main chromosomal
in order to optimize drug delivery both the nebulizers and resistance mechanism to ATM is related to the expression
nebulization technique are also important [77]. In a recent of the efflux pump MexAB-OprM [88]. Thus, the added
metanalysis, nebulized colistin was associated with better value of AVI in P. aeruginosa is lower than for Enterobac-
microbiological outcomes but did not result in any remark- terales, and synergy between ATM and AVI cannot be taken
able changes in the prognosis of patients with VAP [78]. for granted. Likewise, the activity of ATM/AVI activity is
Second, acute kidney injury (AKI) is a concern. This much lower in MBL producing P. aeruginosa as compared
typically occurs 5–7 days after exposure, often as a result with MBL producing Enterobacterales. For example, in one
of acute tubular necrosis [79]. Lodise et al found an AKI study, the susceptibility rate of ATM against MBL–produc-
incidence of 25.1% (RIFLE criteria). Acute kidney injury ing P. aeruginosa strains (53.8%) was only slightly increased
was associated with a higher incidence of mortality and with the addition of AVI (69.2%). On the other hand, ATM,
increased costs [80]. alone or combined with AVI, shows no significant activity
Clinical experience for colistin efficacy against infections against A. baumannii [89].
caused by MBLs is limited. A multicenter study analyzed In vitro study data found that the addition of AVI could
102 cases of bacteremia, 82 of which were caused by NDM- reduce or close the mutant selection window (MSW) of
producing K. pneumoniae or E. coli, and 20 by MIV-produc- ATM in Enterobacterales harboring MBLs. For ATM/AVI
ing strains (70% of which were K. pneumoniae). The over- dosing regimens evaluated in clinical trials, the free drug
all mortality rate in the group treated with the combination concentration was above the mutant prevention concentra-
ATM plus CAZ/AVI was 19%, while the mortality rate in tion values of >90% and >80%, whereas the fraction of time
the group treated with colistin was 59.3% [68]. within the 24 h that the free drug concentration was within
In fact, in a recent report on 343 patients with MBL–pro- the mutant selection window measures were <10% and
ducing Enterobacterales infections, the 30-day mortality rate <20% in plasma and epithelial lining fluid, respectively [90].
was 29.7%. Sensitivity analysis showed that ATM plus CAZ/ An open-label, multicenter Phase 2 trial of ATM/AVI in
AVI, compared with colistin, was independently associated complicated intra-abdominal infections (cIAI) compared 3
with a reduced 30-day mortality rate [81]. dosing regimens for PK/PD target achievement. The regimen
that prevailed, with no safety concerns, was the 500-mg/167-
5.2 Aztreonam/Avibactam (ATM/AVI) mg loading dose followed by 1500-mg/500-mg four times
daily in a 3-h infusion [91].
Aztreonam/avibactam, recently approved in April 2024 by The results of the ASSEMBLE (NCT03580044) study
European Medicines Agency (EMA), combines the inher- showed that 5/12 (41.7%) patients with confirmed MBL–pro-
ent stability of ATM against MBLs with classes A, C and ducing Enterobacterales infections, who received ATM/AVI
some D (OXA-48-like) β-lactamase inhibition offered by ± metronidazole (MTZ), were cured at test of cure (TOC)
AVI. Many carbapenem-resistant Enterobacterales (CRE) versus 0/3 (0%) of those on best available therapy [92].
strains co-produce MBL and serine enzymes that can inac- Aztreonam plus avibactam is indicated for the treatment
tivate ATM. In fact, β-lactamase inhibitors, such as AVI, of adult patients for cIAI, hospital-acquired pneumonia,
zidebactam or nacubactam, protect ATM from hydrolysis including ventilator-associated pneumonia, and complicated
and enhance its anti-MBL activity against Enterobacterales urinary tract infection (cUTI), including pyelonephritis.
and, to a lesser extent, P. aeruginosa [82, 83]. Furthermore, Aztreonam plus avibactam is also indicated for the treat-
a large in vitro broth microdilution study recently con- ment of infections due to aerobic Gram-negative organisms
firmed the potent activity of ATM/AVI against Enterobac- in adult patients with limited treatment options [93]. This
terales isolates. In particular, all carbapenemase-producing resolution also highlights the microbiology data that indicate
1526 C. Hidalgo‑Tenorio et al.

that ATM in combination with AVI may also be of particular reported a nosocomial outbreak by cefiderocol-resistant
utility in infections caused by MBL–producing Enterobac- NDM-1–producing Klebsiella pneumoniae occurring in a
terales and that this combination could therefore address large tertiary care hospital in Florence. Retrospective analy-
an unmet medical need. The most common side effects are sis of cases observed in January 2021–June 2022 revealed
serum transaminase elevation, and diarrhea [91]. Dose selec- that 21/52 were cefiderocol resistant due to the inactivation
tion for ATM/AVI, including adjustments for renal impair- of the cirA siderophore receptor gene. Cefiderocol resist-
ment based on a series of iterative population PK modeling ance in K. pneumoniae has also been associated with the
and probability of target attainment (PTA) analyses, has production of NDM-5 [107]. In another recent report by
recently suggested optimized dosing regimens [94]. Given Lasarte-Rubio et al. [108], cefiderocol resistance in an epi-
the microbiologically active molecules now approved, the demic E. cloacae complex strain was associated with the
use of this combination would be reasonable and could production of the MBL VIM-1, the ESBL SHV-12 and the
replace ATM plus CAZ/AVI. inactivation of a FcuA-like siderophore receptor. Likewise,
high-level cefiderocol resistance in a ST167 E. coli strain
5.3 Aztreonam plus Ceftazidime/Avibactam was associated with the production of NDM-35, showing an
approximate 10-fold increase in hydrolytic activity toward
Aztreonam plus CAZ/AVI has been used as an alternative cefiderocol compared to NDM-1 [109]. Additionally, the
to ATM/AVI in the past due to lack of other therapeutic isolate co-produced a CMY-type β-lactamase, exhibited a
options. In the absence of ATM/AVI in clinical practice, four amino-acid insertion in PBP3, and possessed a trun-
the combination of CAZ/AVI plus ATM can be considered. cated CirA. Moreover, the acquisition of a transferable
However, it is essential that the microbiology laboratory extrachromosomal fec operon has been associated with a
verifies the synergy between AVI (from the CAZ/AVI com- cefiderocol MIC increase in Enterobacterales [110]. The
bination) and ATM, since such synergy does not always number of reports of cefiderocol resistance in P. aeruginosa
occur, and in its absence, the use of this bi-therapy would is lower than for Enterobacterales. Iron transport systems
not be feasible. Aztreonam plus CAZ/AVI has been used as are also typically involved, but in addition to the expression
an alternative to ATM/AVI due to limited options, although of ESBLs or carbapenemases, a major source of resistance
clinical experience is mainly from case reports [95–98]. Fal- development, are the mutations within the catalytic center
cone et al. [99] noted better outcomes with ATM plus CAZ/ of AmpC [111, 112]. Recent in vitro evolution experiments
AVI for NDM- or VIM-producing Enterobacterales bacte- in P. aeruginosa, including XDR high-risk clones, revealed
remia compared to colistin. A retrospective study showed that the most frequent mutations associated with cefidero-
clinical cure rates of 91.6%, 66.7%, and 85.7% for ATM col resistance were those on piuC, fptA and pirR, related to
plus CAZ/AVI alone, with polymyxin, and with fosfomycin, iron uptake [113]. Additionally, an L320P AmpC mutation
respectively, in NDM and OXA-48 infections [100]. Timsit was selected in multiple lineages, and cloning confirmed its
et al reported clinical cure in 5 of 7 NDM-producing Entero- major impact on cefiderocol (but not ceftolazane/tazobactam
bacterales cases with this combination [101]. or CAZ/AVI) resistance [113]. Mutations in CpxS and PBP3
A systematic review by Mauri et al found a 19% 30-day were also documented. Cefiderocol resistance in A. bauman-
mortality rate for ATM plus CAZ/AVI, lower than the 44 nii has been shown to be multifactorial and dependent on
% in the control group (odds ratio 0.33; 95% CI 0.13–0.66) the interplay of the expression of β-lactamases, siderophore
[82] although effectiveness was low against MBL–producing receptors and PBP3 mutations [114].
P. aeruginosa. A meta-analysis showed ATM plus CAZ/AVI Hypotheses suggest that undetected hetero-resistance of
had a lower 30-day mortality risk compared to polymyxins Acinetobacter to cefiderocol – defined as the presence of
(risk ratio 0.51; 95% CI, 0.34–0.76) [102]. resistant subpopulations within a majority population sus-
ceptible to this agent – might explain the higher all-cause
5.4 Cefiderocol mortality rates observed in the CREDIBLE-CR study among
patients with infections caused by this organism [115, 116].
Cefiderocol is a novel siderophore cephalosporin with activ- However, a subsequent study focused exclusively on car-
ity against a large range of multi-resistant organisms, includ- bapenem-resistant isolates of the Acinetobacter calcoaceti-
ing MBL producers. cus-baumannii complex, which were cultured from patients
Resistance to cefiderocol has been documented in several treated with cefiderocol in the CREDIBLE-CR study. This
bacterial species and is generally mediated by the interplay study employed the methodology Population Analysis Pro-
of the expression of β-lactamases with potent cephalospori- filing (PAP) and surprisingly, for infections caused by PAP-
nase activity, such as several extended spectrum beta lacta- hetero-resistant isolates, the clinical cure rate was higher and
mases (ESBLs) or carbapenemases, with mutations in iron mortality lower than for infections due to PAP-susceptible
uptake systems [103–105]. Coppi et al. [106] have recently or PAP-resistant isolates [117]. The underlying causes of
Metallo-β-Lactamase Treatment 1527

cefiderocol hetero-resistant phenotypes remain poorly under- differences were likely due to deaths occurring within the
stood. In other studies involving K. pneumoniae, hetero- first 72 h and after 29 days, as well as the fact that patients
resistance has been linked to mutations in cirA (which codes in the cefiderocol arm were more severely ill, with higher
for a siderophore receptor) [118] and to blaSHV-12 ampli- rates of ICU admission, septic shock, and mechanical ven-
fication [119]. Cefiderocol hetero-resistance has also been tilation. All these factors are known independent predictors
hypothesized to be related to bacterial recurrence in a patient of mortality [128].
with bacteremia caused by caused NDM-5–producing K. The efficacy of combination treatment compared to cefi-
pneumoniae [120]. Importantly, the standard methodology derocol monotherapy remains unresolved. In carbapenem-
for defining hetero-resistance (population analysis profiling) resistant A. baumannii (CRAB) infections, a meta-analysis
lacks clinical validation as a predictor of patient outcomes, by Onorato et al. evaluated cefiderocol monotherapy and
both clinically and microbiologically. At present, correlating the combination therapy among seven studies. They found
hetero-resistance to cefiderocol with clinical outcomes in a significantly lower mortality rate among patients receiv-
patients treated with this cephalosporin remains challenging. ing cefiderocol in monotherapy as compared to treated
Specific tissue penetration data are available for the res- with combination regimens. However, these findings were
piratory system: in healthy volunteers after a single 2-g not confirmed in the sub-analysis including only patients
intravenous (IV) dose, the drug penetrates into epithelial with bloodstream infections nor in the analysis including
lining fluid (ELF) with geometric mean concentration ratios, patients with pneumonia [129]. A recent review also found
over 6 h, ranging from 0.0927 to 0.116 mg/L for ELF and no significant difference in terms of mortality, microbiologi-
total plasma. In patients with VAP, the geometric mean cal eradication and clinical cure between monotherapy and
ELF concentration of cefiderocol was 7.63 mg/L at the end combination therapy [130, 131].
of infusion, and 10.40 mg/L 2 h later. The ELF/unbound The most frequently reported treatment-emergent adverse
plasma concentration ratio was 0.212 (21.2 %) at the end of events were diarrhea, pyrexia, and vomiting. Liver enzyme
infusion and 0.547 after 2 h, suggesting delayed lung distri- increases or clotting abnormalities occurred more frequently
bution, with concentrations sufficient to treat Gram-negative in the cefiderocol group [125]. Treatment-emergent adverse
bacteria [121, 122]. events reported in at least 5% of patients in either treatment
Although few reports have evaluated the efficiency of group were generally balanced across treatment groups.
newly developed antibiotics in relation to the inoculum Four of 148 (3%) patients in the cefiderocol group and four
effect, this phenomenon could be responsible for clinical of 150 (3%) patients in the meropenem group developed
failure and the selection of resistant bacteria. A recent study Clostridium difficile infection or colitis [126].
investigated the impact of inoculum size on the MICs of In randomized clinical trials conducted with cefiderocol
cefiderocol and new β-lactams/β-lactamase inhibitors. When in patients with nosocomial pneumonia, bacteremia, and
the inoculum increased to 1­ 07 colony-forming units (CFU)/ sepsis or complicated urinary tract infections (cUTI), cefi-
mL, all molecules were affected, particularly cefiderocol derocol demonstrated numerically higher rates of clinical
and imipenem-relebactam. In contrast, CAZ/AVI remained cure and microbiological eradication compared to compara-
only mildly affected [123]. Another recent paper demon- tors against MBL–producing pathogens, including entero-
strated that NDM producers exhibited lower susceptibil- bacteria and non-fermenters [132]. The benefit in outcomes
ity to cefiderocol and ATM/AVI compared to VIM or IMP was observed across different genera or species and cefi-
producers. Inoculum effects on cefiderocol and ATM/AVI derocol MIC levels (up to 4 μg/mL), demonstrating effective
were observed in over 90% of susceptible carbapenemase- eradication of highly carbapenem-resistant bacteria. A simi-
producing Enterobacteriaceae isolates [124]. lar observation can be made for NDM-type carbapenemases,
Pivotal clinical trials [125, 126] demonstrated the efficacy as the clinical cure rate (56.2% [9/16]) for NDM-producing
of cefiderocol monotherapy against infections caused by infections was lower than for non-NDM enzymes (100%
MBL–producing Gram-negative bacteria. Overall, the rates [8/8]) [101, 127].
of clinical cure (70.8% [17/24]), microbiological eradication A recent narrative case series by a French group docu-
(58.3% [14/24]), and all-cause mortality at 28 days (12.5% mented the experience with a cefiderocol regimen in treating
[3/24]) were favorable compared to the comparator arms in a cohort of 16 critically ill patients with difficult-to-treat
the trials. These included the option of prescriber-judged nosocomial infections caused by MDR Gram-negative bacte-
best available therapy and high-dose meropenem, with rates ria [133]. Within this cohort, four patients with five isolates
of 40.0% (4/10), 30.0% (3/10), and 50% (5/10), respectively of MBL–producing Gram-negative bacteria (all character-
[127]. ized as VIM) were highlighted. All these patients received
A higher mortality rate was observed in patients with Aci- cefiderocol treatment, primarily as monotherapy, except 1
netobacter infections, which was 50% compared to 18% in patient with A. baumannii-induced ventilator-associated
those who received the best available therapy [125]. These pneumonia in whom it was combined with tigecycline.
1528 C. Hidalgo‑Tenorio et al.

Importantly, none of these patients treated with cefiderocol shock) and epidemiological characteristics (i.e., age, immu-
for infections caused by MBL–producing Gram-negative nosuppression, recent admissions, living in a nursing home,
bacteria died during their ICU stay. In another case series, and administration of antibiotics in the last 3 months); local
among 18 evaluable patients with infections caused by cefi- epidemiology considering susceptibility rates and resistance
derocol-susceptible MBL–producing CRE (clinical cure was mechanisms of the main microorganisms isolated from the
72.2 % [13, 18], eradication at end of treatment was 77.8 % hospital center; and the type and source of the infection
[14, 18], and 28-day mortality was 22.2 % [4 of 18 patients: (high inoculum, such as pneumonia, CNS, and bacteremia;
4 of 16 in NDM-producing CRE vs 0 of 2 in VIM-producing or low inoculum, such as urinary tract infection or skin and
CRE]) [134]. soft tissue infection) [136].

6 Guideline Recommendations
7 New Approaches
Clinical practice guidelines from various scientific societies
have addressed this issue. In 2022, the European Society Several new β-lactamase inhibitors combined with different
for Clinical Microbiology and Infectious Diseases (ESC- β-lactams have recently been introduced in clinical prac-
MID) recommended the use of cefiderocol for the treat- tice. The already commented successful combination of AVI
ment of severe infections caused by MBL–producing CRE with ATM for treating MBL–producing organisms is not
or those resistant to all other antibiotics, including CAZ/ similar to the situation with other inhibitors such as vabor-
AVI and meropenem/vaborbactam (low-level evidence) bactam (combined with meropenem) or relebactam (com-
[135]. According to ESCMID, for patients with non-severe bined with imipenem), as they are not active against class B
CRE infections, it is recommended to use an antibiotic that β-lactamases, but only class A and C enzymes.
has been shown to be effective in vitro, and the choice of
antibiotic should be based on the individual case and the 7.1 Cefepime/Zidebactam (WCK 5222)
source of the infection. In case of urinary tract infections,
aminoglycosides, such as plazomicin, are recommended over Cefepime/Zidebactam (WCK 5222) is a singular combi-
tigecycline (conditional recommendation and low evidence). nation of cefepime with a bicyclo-acylhydrazide zidebac-
Tigecycline is not recommended for bacteremia or nosoco- tam that acts as a β-lactam enhancer mediating multiple
mial or ventilator-associated pneumonia. Finally, guidelines penicillin-binding proteins (PBP) binding. Zidebactam not
suggested that if tigecycline was deemed necessary for treat- only protects cefepime from hydrolysis by certain serine
ing pneumonia, it should be administered at high doses (low β-lactamases but also has stand-alone antibacterial activity
certainty of evidence) [135]. due to its potent PBP2 binding in all Gram-negative bacte-
According to IDSA guidelines, the preferred antibiotics ria (Enterobacterales and P. aeruginosa) [137, 138]. Several
for infections outside the urinary tract caused by NDM-pro- studies have demonstrated the potent activity of cefepime/
ducing CRE are CAZ/AVI in combination with ATM, or zidebactam against a range of carbapenem-resistant patho-
cefiderocol as monotherapy. In cases of P. aeruginosa-diffi- gens, including VIM/NDM-expressing P. aeruginosa iso-
cult to treat resistance (PA-DTR) isolates producing MBL, lates, which co-amplify efflux and impermeability [139,
the recommended treatment is cefiderocol monotherapy. 140].
Cefiderocol should be reserved for CRAB infections unre-
sponsive to other antibiotics or when other agents cannot be 7.2 Taniborbactam
used due to intolerance or resistance. When used for CRAB
infections, cefiderocol should be included in a combination Taniborbactam (formerly VNRX-5133) is a cyclic boronate
regimen (https://​www.​idsoc​iety.​org/​pract​icegu​ideli​ne/​amr-​ with a broad spectrum of activity, including KPC, OXA-48
guida​nce/) [131]. and MBLs (VIM and most NDM, but not IMP) and is the
Given this situation, hospital antimicrobial stewardship first inhibitor against all classes of β-lactamases. It uses a
programs play a fundamental role in the recommendation different mechanism to inhibit both SBLs and MBLs. For
and appropriateness of empirical or targeted antibiotic MBLs, it acts as a reversible competitive inhibitor with low
treatment with cefiderocol in patients with suspected or inhibition constants (Ki) and rapid dissociation. Tanibor-
confirmed infection with MBL–producing Gram-negative bactam is being developed in combination with cefepime or
bacilli. Recommendations take into account the following meropenem to treat severe infections caused by MDR patho-
premises: patients’ clinical situation (febrile, septic or in gens (CRE and carbapenem-resistant P. aeruginosa) [141].
Metallo-β-Lactamase Treatment 1529

7.3 Xeruborbactam assays (gradient strips, commercial broth microdilution) are

commonly used when testing cefiderocol. It also important
Xeruborbactam (formerly QPX7728) is an ultra-broad- to consider that the activities of cefiderocol and ATM/AVI
spectrum cyclic boronic acid beta-lactamase inhibitor against MBL–producing Gram-negative bacteria is highly
(BLI) with activity against SBLs and MBLs. Preliminary dependent on the species and the concrete enzyme involved,
data have shown that the meropenem/QPX7728 combination so treatment algorithms should be individualized (see
appears to CRAB, producing carbapenem-hydrolyzing class Fig. 1). There are also growing reports on emerging resist-
D β-lactamases (CHDLs), NDM and KPC. Overall, it seems ance to these novel beta-lactam combinations, so clinical
to have excellent affinity for important carbapenemases such microbiology laboratories must have reliable susceptibility
as KPC-2, IMP-1, VIM-1, NDM-1, OXA-23 and OXA-48 testing procedures for these novel agents at their disposal.
[142]. While the choice of cefiderocol versus ATM/AVI or ATM
plus CAZ/AVI will depend on several of the above vari-
ables, either of these options are preferable to colistin, unless
8 Expert Opinion resistance is proved for both options (see Fig. 1).
From a clinical perspective, understanding the efficacy
Delivering a timely and appropriate empirical or targeted and safety of different treatment options is essential for
treatment against Gram-negative MDR bacteria, such as managing infections caused by MBL–producing Gram-
Enterobacterales, A. baumannii, and P. aeruginosa is criti- negative bacteria. Stewardship teams have to promote the
cal. A comprehensive clinical algorithm for the choice of prudent use of antimicrobials in an effort to achieve a bal-
treatment of infections caused by MBL–producing Gram- ance between effectiveness, in terms of clinical response and
negative bacteria is shown in Fig. 1. outcomes, and adverse events. Given its PK/PD characteris-
From a microbiological perspective, the choice of treat- tics, reported toxicities and poor clinical outcomes, colistin
ment for infections caused by MBL–producing Gram-neg- may be an option only when new-generation antimicrobials
ative bacteria is crucial. The prevalence of carbapenemase- are not available or are inactive, or when cross-reactivity in
producing microorganisms, particularly of the MBL type, patients with β-lactam allergy is likely.
varies geographically and depends on the microbial species Aztreonam plus avibactam could be an acceptable option
involved. In P. aeruginosa, MBLs are the most prevalent in infections caused by MBL–producing Enterobacterales,
enzyme types when the organism produces carbapenemases, for which efficacy and safety results from Phase 3 trials
but in some regions this is not the main mechanism of car- showed a percentage (95% CI) of patients with clinical cure
bapenem resistance in this organism. The wide spectrum of 41.7 (18.0–68.8) and the effectiveness of the combination
of activity and associated co-resistances mean that an early in clinical practice must be tested in observational studies. In
and accurate diagnosis is essential to ensure appropri- view of the recent approval of these new molecules, it would
ate antimicrobial therapy. However, assessing the in vitro be advisable to utilize this new combination instead of ATM
activity of anti-MBL antimicrobials remains challenging, plus CAZ/AVI. In case of infections due to PA-DTR, this
especially when evaluating synergism between ATM and antibiotic does not work because AVI does not contribute to
CAZ/AVI (not routinely performed) or AVI/ATM (without restoring ATM activity. Cefiderocol has a key role in treat-
a breakpoint according to EUCAST, with the exception of ing infections caused by MBL–producing P. aeruginosa and
Enterobacterales, for which the EUCAST breakpoints define MBL–producing CRE in complex or critically ill patients,
susceptible as ≤4 mg/L and resistant as >4 mg/L) [37] and given its novel mechanism of action that promotes activity
cefiderocol for susceptibility testing. A standardized method in the presence of these enzymes, active efflux pumps, or
for studying the in vitro combination of antimicrobial agents porin loss.
is imperative because the results of the various assays cur- The use of all antimicrobials should be personalized for
rently in use are not always equivalent. Moreover, enhanc- each patient or episode. In the case of cefiderocol, moni-
ing technical capabilities for studying synergy in vitro will toring involves the strict adaptation of the dosing regimen
lead to a better understanding of the correlation between to the different ranges of renal function to achieve a 90%
microbiological data and clinical outcomes. As for testing probability of target attainment of 75% fT>MIC [143–146].
cefiderocol, the main limitation in practice derives from the This should avoid or at least predict the development and
need to use an iron-depleted medium, which is not routinely selection of resistance in vivo [147], usually generated by
available in clinical laboratories; this has also prevented the combined expression of various mechanisms [103].
manufacturers of semi-automated susceptibility testing sys- Some clinical guidelines [131, 135, 148] propose AVI/
tems from preparing panels with cefiderocol as one of the ATM as the first choice against MBL producers [149, 150].
test drugs. For both reasons, other standardized approaches However, in certain clinical situations cefiderocol is con-
(basically, the disk diffusion assay) or specific commercial sidered the first choice, due to its lower MIC values with
1530 C. Hidalgo‑Tenorio et al.

Fig. 1  Flowchart of treatment options for infections caused by a lack of standardized synergy testing methods. c Avibactam does not
metallo-β-lactamase-producing Gram-negative bacteria. CRAB: significantly contribute to increased aztreonam activity in aztreonam-
carbapenem-resistant Acinetobacter baumannii; CRE: carbapenem- resistant P. aeruginosa and is not usually an adequate option for
resistant Enterobacterales; HD: high doses; refers to the need to use PA-DTR. The CHMP positive opinion, highlights its utility in infec-
loading doses of certain drugs and/or doses higher than those usually tions caused by MBL–producing Enterobacterales. d Combined: The
recommended by the technical sheet; MBL: metallo-β-lactamases. a combination could depend on the source of infection; recommended
Ideally the choice of treatment should be guided by appropriate sus- in hospital-acquired pneumonia (HAP) or ventilator-associated pneu-
ceptibility testing results. According to current trends of resistance to monia (VAP), bloodstream infections, cIAI and cUTI. The combined
the novel β-lactams, this is particularly relevant in the case of ATM/ treatment option for colistin includes the possibility of its inhalation
AVI for NDM-producing Gram-negative bacilli and for all MBL–pro- route through aerosol therapy in pneumonia, along with other sys-
ducing P. aeruginosa. b Aztreonam/avibactam, approved in April temic antibiotics. Combinations that increase nephrotoxicity or other
2024, is not yet available for clinical use. Ceftazidime/avibactam adverse effects should be avoided." e Eravacycline is not yet (April
plus aztreonam could be used as an alternative, although some limit- 2024) available. f Combined with aminoglycosides in cUTI. g ATM/
ing factors should be considered: (i) there is no evidence of clinical AVI is approved for the treatment of MBL–producing Enterobacte-
equivalence with aztreonam-avibactam, (ii) there is a risk of emer- rales and for the treatment of infections caused by aerobic Gram-neg-
gence of resistant mutants if dosing is not optimal, and (iii) there is ative organisms in adult patients with limited treatment options.

higher activity and reported efficacy against MBL–produc- second agent for A. baumannii (see Fig. 1). All decisions
ing P. aeruginosa [151, 152] compared to Enterobacterales must be comprehensive and taken under the guidance of the
(see Fig. 1). In short, when an infection is identified as stewardship team.
being caused by MBL–producing Gram-negative bacteria Combining antibiotics might be a useful strategy to
(e.g., NDM, VIM or IMP), which typically cause cross- improve the success rate and efficacy of these drugs and may
resistance phenomena between β-lactams and co-resistance prevent the emergence of resistance to new agents, although
to other antibiotic families, the therapeutic options currently some authors believe that it may lead to increased toler-
include cefiderocol monotherapy or AZT/AVI. Actually, in ance to antibiotics and favor the development of resistance
the absence of comparative studies between cefiderocol and [153]. Cefiderocol could also be an option as an empirical
AVI/ATM in infections caused by MBL–producing Entero- choice for early active treatment of well selected patients
bacterales, it is difficult to establish the order of priority with severe infections and resistance risk factors in areas
in the choice between the two drugs, so the decision will endemic for more than one MBL–producing Gram-negative
depend on local epidemiology, microorganism type, and organism (Enterobacterales, P. aeruginosa or A. bauman-
the MBL expressed. Considering the in vitro and clinical nii). In such a situation, rapid de-escalation to another agent
data discussed above, cefiderocol could be a first option for is crucial whenever possible, based on rapid and detailed
MBL–producing P. aeruginosa and in combination with a microbiological characterization of the causative pathogen,
Metallo-β-Lactamase Treatment 1531

and following recommendations by stewardship team. from Shionogi, Gilead Sciences, Janssen, Merck Sharp & Dohme, and
Finally, therapeutic alternatives to antibiotics are emerging, ViiV Healthcare. LM-M has been a consultant for MSD, Shionogi and
Advanz, has served as a speaker for MSD, Pfizer and Shionogi and
such as bacteriophage therapy. Nevertheless, the clinical use has received research grants from Pfizer, MSD and Shionogi. MR-A
of phages (usually as personalized treatment) is still limited has conducted consulting work for Shionogi and Viatris. MR-A has
by their excessive specificity and by technical preparation served as a speaker for Pfizer, Gilead Sciences and Shionogi. AO has
issues. In summary, cefiderocol in monotherapy or combina- received research grants and speakers fees from Shionogi, Pfizer and
MSD. GB has been a consultant for Pfizer, Astellas, Roche, MSD,
tion, and AZT/AVI are a suitable option for MBL–producing Shionogi and Advanz, has served as a speaker for MSD, Pfizer, Roche,
Gram-negative infection. Further innovation and research Advanz and Shionogi and has received research grants from Pfizer,
with new antimicrobial molecules in monotherapy or com- Advanz and MSD. MSL has received remuneration for lectures and
bination therapy will be decisive in addressing this contro- advisory boards (Advanz Pharma, Angelini Pharma, Janssen, Menar-
ini, MSD, Pfizer, Shionogi, Viatris) and educational grants (Gilead,
versial matter. Tedec-Meiji).

Author Contributions All authors have contributed to the conception

9 Conclusion of the work. All authors wrote the original draft and performed sub-
stantial contributions to the final manuscript. All authors reviewed and
approved the final manuscript for submission. All authors agreed to be
Infections caused by MBL–producing Gram-negative bac- accountable for all aspects of the work.
teria present a significant clinical challenge due to their
resistance mechanisms and the limited therapeutic options Ethics Approval, Informed Consent, and Data Availability Not appli-
cable for this review.
available. Our review highlights the critical roles of new
therapeutic agents, specifically cefiderocol and the com-
Open Access This article is licensed under a Creative Commons Attri-
bination of ATM with AVI, in treating these infections. bution-NonCommercial 4.0 International License, which permits any
Cefiderocol has shown efficacy against a wide range of non-commercial use, sharing, adaptation, distribution and reproduction
multidrug-resistant organisms, including MBL produc- in any medium or format, as long as you give appropriate credit to the
ers Enterobacterales and P. aeruginosa, and is particu- original author(s) and the source, provide a link to the Creative Com-
mons licence, and indicate if changes were made. The images or other
larly recommended for P. aeruginosa and for complex third party material in this article are included in the article's Creative
or critically ill patients. The ATM/AVI combination also Commons licence, unless indicated otherwise in a credit line to the
offers potent activity against MBL–producing pathogens, material. If material is not included in the article's Creative Commons
especially Enterobacterales. However, colistin should be licence and your intended use is not permitted by statutory regula-
tion or exceeds the permitted use, you will need to obtain permission
reserved as a last-resort option due to its nephrotoxicity directly from the copyright holder. To view a copy of this licence, visit
and the emergence of resistance. Further research is nec- http://​creat​iveco​mmons.​org/​licen​ses/​by-​nc/4.​0/.
essary to optimize treatment strategies and minimize the
development of resistance. Comprehensive antimicrobial
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Authors and Affiliations

Carmen Hidalgo‑Tenorio1,10 · German Bou2,9 · Antonio Oliver3,9 · Montserrat Rodríguez‑Aguirregabiria4 ·

Miguel Salavert5 · Luis Martínez‑Martínez6,7,8,9

5
* Carmen Hidalgo‑Tenorio Infectious Diseases Unit, Hospital Universitario y Politécnico
[email protected] La Fe, Valencia, Spain
6
Luis Martínez‑Martínez Microbiology Unit, Hospital Universitario Reina Sofía,
[email protected] Córdoba, Spain
7
1 Department of Agricultural Chemistry, Soil Sciences
Hospital Universitario Virgen de las Nieves de Granada,
and Microbiology, Universidad de Córdoba, Córdoba, Spain
Instituto de Investigación Biosanitario de Granada (IBS-
8
Granada), Granada, Spain Instituto Maimónides de Investigación Biomédica de
2 Córdoba (IMIBIC), Córdoba, Spain
Servicio de Microbiología, Complejo Hospitalario
9
Universitario A Coruña, A Coruña, Spain Centro de Investigación Biomédica en Red de Enfermedades
3 Infecciosas (CIBERINFEC), Instituto de Salud Carlos III,
Servicio de Microbiología y Unidad de Investigación,
Madrid, Spain
Hospital Son Espases, IdISBa, Palma de Mallorca, Spain
10
4 Departamento de Medicina, Universidad de Granada,
Critical Care Department. Hospital, Universitario La
Granada, Spain
Paz. (IdiPaz), Madrid, Spain