REVIEW

Cefiderocol: A Novel Agent for the Managementof Multidrug-Resistant Gram-Negative Organisms

Janet Y. Wu . Pavithra Srinivas . Jason M. Pogue

Received: December 16, 2019 / Published online: February 18, 2020� The Author(s) 2020

ABSTRACT

Cefiderocol, formerly S-649266, is a first in itsclass, an injectable siderophore cephalosporinthat combines a catechol-type siderophore andcephalosporin core with side chains similar tocefepime and ceftazidime. This structure and itsunique mechanism of action confer enhancedstability against hydrolysis by many b-lacta-mases, including extended spectrum b-lacta-mases such as CTX-M, and carbapenemasessuch as KPC, NDM, VIM, IMP, OXA-23, OXA-48-like, OXA-51-like and OXA-58. Cefiderocol’sspectrum of activity encompasses both lactose-fermenting and non-fermenting Gram-negativepathogens, including carbapenem-resistant

Enterobacterales. Cefiderocol recently receivedUS Food and Drug Administration approval forthe treatment of complicated urinary tractinfections, including pyelonephritis, and iscurrently being evaluated in phase III trials fornosocomial pneumonia and infections causedby carbapenem-resistant Gram-negative patho-gens. The purpose of this article is to reviewexisting data on the mechanism of action,microbiology, pharmacokinetics, pharmacody-namics, efficacy, and safety of cefiderocol toassist clinicians in determining its place intherapy.

Keywords: Cefiderocol; Cephalosporin; CRE;Siderophore

Enhanced Digital Features To view enhanced digitalfeatures for this article go to https://doi.org/10.6084/m9.figshare.11792034.

J. Y. Wu (&) � P. SrinivasDepartment of Pharmacy, Cleveland Clinic,Cleveland, OH, USAe-mail: wuj5@ccf.org

J. M. PogueCollege of Pharmacy, University of Michigan, AnnArbor, MI, USA

Infect Dis Ther (2020) 9:17–40

https://doi.org/10.1007/s40121-020-00286-6

Key Summary Points

Cefiderocol is a first in its class, aninjectable siderophore cephalosporin withpotent in vitro activity againstcarbapenem-resistant Enterobacteriaceaeand drug-resistant non-fermenting Gram-negative bacilli.

Cefiderocol was recently US FDA-approvedfor the treatment of complicated urinarytract infections (cUTI), includingpyelonephritis, and is being evaluated forthe treatment of nosocomial pneumoniaand carbapenem-resistant infections.

Its unique mechanism of action allows forhigh intracellular penetration into theperiplasmic space and increased stabilityto many b-lactamases including bothserine-type (KPC, OXA) and Ambler classB metallo-b-lactamases (VIM, IMP, NDM).

Cefiderocol has an important place intherapy for cUTI, but further data arenecessary to determine its place in therapyfor other systemic infections, such aspneumonia and bloodstream infections.

INTRODUCTION

The emergence of carbapenem resistance inEnterobacterales, Pseudomonas aeruginosa, andAcinetobacter baumannii is an urgent threat toglobal public health [1]. These Gram-negativeorganisms are common pathogens in a varietyof serious infections, including intra-abdominalinfections, pneumonia, urinary tract infections,and bloodstream infections (BSI) [2]. The pres-ence of multi-drug resistance complicates themanagement of these infections due to thelimited treatment options available. Histori-cally, antibiotic options for multi-drug resistant(MDR) Gram-negative infections have includedaminoglycosides, polymyxins, and/or tigecy-cline. Unfortunately, these agents possess

significant disadvantages, including toxicities,sub-optimal pharmacokinetics at target sites ofinfection, and poor outcome data [3]. While theantimicrobial pipeline has recently produced anumber of game-changing agents, gaps in thearmory are still present. Most recent additionsto the armamentarium have targeted activityagainst MDR P. aeruginosa (ceftolozane/ta-zobactam, ceftazidime/avibactam, imipenem/relebactam), and KPC-producing (ceftazidime/avibactam, meropenem/vaborbactam, and imi-penem/relebactam) and OXA-48-like (cef-tazidime/avibactam) carbapenem-resistantEnterobacterales (CRE). Additionally, pla-zomicin, a novel aminoglycoside, displaysenhanced activity against Enterobacterales,including CRE. However, antibacterials withactivity against Ambler Class B metallo b-lacta-mases (NDM, VIM, IMP) are lacking. Further-more, the novel b-lactamase inhibitorcombinations provide no clinically relevantprotection for the parent b-lactam compoundagainst other class D carbapenemases, such asOXA-23, OXA 40, OXA-51-like, which are thepredominant enzymes driving carbapenemresistance in A. baumannii [4]. Compoundingthe problem, non-b-lactamase-mediated mech-anisms of resistance, such as mutations causingporin channel depletion or efflux pump up-regulation, are becoming a growing threat inthe development of carbapenem resistance, andthe novel agents do not fully address this need[5, 6]. Similarly, the recent additions to thearmamentarium fail to address other problem-atic non-fermenting Gram-negative bacilli, suchas Stenotrophomonas maltophilia and Burkholderiaspp., which are inherently associated with highrates of b-lactam resistance.

Cefiderocol is a newly US FDA-approved, firstin its class, siderophore cephalosporin withpotent in vitro activity against CRE and drug-resistant non-fermenting Gram-negative bacilli.The purpose of this article is to review existingdata on the mechanism of action, microbiology,pharmacokinetics, pharmacodynamics, efficacyand safety of cefiderocol.

18 Infect Dis Ther (2020) 9:17–40

DATA SOURCES

Literature for this review was obtained througha search of MEDLINE for all materials contain-ing the name ‘‘S-649266’’ or ‘‘cefiderocol’’.Additional sources were obtained through clin-icaltrials.gov, FDA briefing document, andconference proceedings and publishedabstracts. This article is based on previouslyconducted studies and does not contain anystudies with human participants or animalsperformed by any of the authors.

CHEMISTRY AND MECHANISMOF ACTION

To appreciate the unique mechanism(s) ofaction of cefiderocol, it is important to under-stand the role of iron in host immunity andinfection. Iron, in its insoluble ferric form(Fe3?), is an essential nutrient for various cel-lular processes such as respiration and DNAreplication. Under physiological conditions inhumans, iron metabolism and distribution is atightly regulated process. The majority of iron iscomplexed with hemoglobin within erythro-cytes. Any extracellular iron is tightly bound toproteins, such as transferrin, or with a loweraffinity to albumin, citrate, and amino acidswhen transferrin-binding capacity may beexceeded. In the setting of an infection, ironsequestration is further increased by lactoferrin,a protein that maintains iron-binding capacityin acidic environments, as well as peptides, suchas hepcidin, and cytokines, such as interferongamma, tumor necrosis factor alpha, inter-leukin-1 and Interleukin-6 [7].

Similar to humans, microorganisms alsorequire iron for important cellular redox pro-cesses. In order to survive under iron-depletedconditions in human hosts, pathogens possessvarious pathways for heme uptake and non-heme iron-acquisition mechanisms. One suchmechanism is the production and subsequentextracellular release of molecules called side-rophores that scavenge for free ferric iron andundergo re-uptake into the cell as a side-rophore–iron complex via iron transporterchannels. Siderophores are classified into three

general types: hydroxamate, carboxylate, andcatecholate. Hydroxamate- and carboxylate-type siderophores are commonly produced byfungi and some bacteria, while catecholatesiderophores are primarily produced by bacte-ria. For example, the enteric Gram-negativebacteria, Escherichia coli, produces enterobactin,a catechol siderophore with a high affinity forFe3?, while P. aeruginosa produces a combina-tion of pyoveridine, a hydroxamate-type, andpyochelin, a catecholate-type, siderophores [8].

Cefiderocol (S-649266), a novel combinationof a catechol-type siderophore and a cephalos-porin antibiotic, utilizes the siderophore–ironcomplex pathway to penetrate the outer mem-brane of Gram-negative organisms in additionto normal passive diffusion through membraneporins. The chemical structure of cefiderocolcontains a cephalosporin core with side chainssimilar to ceftazidime and cefepime. Theaminothiazole ring and carboxypropyl-oxy-imino group attached to the 7-position sidechain confer enhanced activity against Gram-negative bacilli, including P. aeruginosa and A.baumannii. A catechol 2-chloro-3,4-dihydroxy-benzoic acid moiety on the 3-position of the R2side chain functions as the siderophore mimic,by chelating extracellular iron and by facilitat-ing enhanced uptake into bacterial periplasmicspace via iron transporter channels in the outermembrane. Additionally, a pyrridoline ringbound to the catechol moiety confers zwitteri-onic properties, similar to those of cefepime,that enhance water solubility of the molecule[9, 10]. Once within the periplasmic space,cefiderocol dissociates from the iron and bindsto penicillin-binding proteins (PBP), primarilyPBP3, to inhibit peptidoglycan synthesis.Compared to ceftazidime, cefiderocol hasdemonstrated significantly lower IC50s (50%inhibitory concentrations) and a higher affinityfor PBP3 in strains of E. coli, Klebsiella pneumo-niae, P. aeruginosa and A. baumannii. Further-more, the combined structure of acephalosporin and a catechol moiety appears toconfer enhanced stability against hydrolysis bymany b-lactamases, including extended spec-trum b-lactamases (ESBLs), such as CTX-M, andcarbapenemases, such as KPC, NDM, VIM, IMP,OXA-23, OXA-51-like and OXA-58 [11].

Infect Dis Ther (2020) 9:17–40 19

IN VITRO ACTIVITY

Cefiderocol has potent in vitro activity againstvarious lactose-fermenting enteric Gram-nega-tive bacilli, including E. coli, Klebsiella spp., En-terobacter spp., Proteus spp., Providencia spp.Salmonella spp., Yersinia spp., and Vibrio spp., aswell as non-fermenting organisms, such asAcinetobacter spp., Pseudomonas spp., Burkholde-ria spp., and Stenotrophomonas maltophilia.Cefiderocol has also demonstrated in vitroactivity against Haemophilus spp., Moraxellacatarrhalis, and Bordetella parapertussis, and theintrinsically multidrug-resistant Elizabethkingiameingoseptica. However, activity against aerobicGram-positive and anaerobic organisms iscomparatively weaker. High minimum inhibi-tory concentrations (MICs) have been observedagainst most aerobic Gram-positive and anaer-obic Gram-positive and Gram-negative organ-isms [11].

Cefiderocol is currently being evaluated inclinical trials for the treatment of carbapenem-resistant Gram-negative infections, includingEnterobacterales, P. aeruginosa and A. bauman-nii. MICs of cefiderocol required to inhibitgrowth in 50% (MIC50) and 90% (MIC90) ofGram-negative isolates range from 0.12 to0.5 lg lg/mL and from 0.5 to 4 lg lg/mL,respectively. A comparison of cefiderocol MIC50

and MIC90 to meropenem, ceftazidime/avibac-tam (CAZ/AVI) and ceftolozane/tazobactam(TOL/TAZ) against various Gram-negative iso-lates is summarized in Table 1. Overall, cefide-rocol MICs ranged from B 0.002 to 128 lg/mLfor all Enterobacterales, compared to0.008–8 lg/mL for a subset of carbapenem-re-sistant Enterobacterales from a compilation ofworldwide isolates. In surveillance studies,cefiderocol demonstrated more potent in vitroactivity against carbapenem-resistant Enter-obacterales, A. baumannii and P. aeruginosa,compared to meropenem, CAZ/AVI and TOL/TAZ [10]. Cefiderocol inhibited[ 98% of CAZ/AVI and TOL/TAZ non-susceptible Enterobac-terales and all CAZ/AVI and TOL/TAZ non-sus-ceptible P. aeruginosa isolates at MICs B 4 lg/mL, the provisional susceptibility breakpointfrom the Clinical and Laboratory Standards

Institute (CLSI) [12]. Additionally, cefiderocolhas also demonstrated potent in vitro activityagainst S. maltophilia with an MIC90 of 0.25 lg/mL, and low MICs against Burkholderia cepacia(MIC90 0.12–0.5) [12, 13].

As previously stated, the CLSI has establishedprovisional MIC breakpoint standards of B 4(susceptible), 8 (intermediate), and C 16 lg/mL(resistant) for cefiderocol against Enterobac-terales, P. aeruginosa, Acinetobacter spp., and S.maltophilia. One key differentiating feature ofsusceptibility testing for cefiderocol is that itrequires an iron-depleted medium, typically aniron-depleted cation -adjusted Mueller–Hintonbroth (ID-CAMHB) [14]. The presence of iron inCAMHB may interfere with organism uptake ofcefiderocol in vitro, thereby resulting inincreased cefiderocol MICs. Use of an iron-de-pleted medium mimics the physiological stateof iron-depletion in the human host, and hasdemonstrated good correlation with in vivoefficacy [15].

In vitro studies of the stability of cefiderocolagainst clinically relevant carbapenemases havedemonstrated that the compound is relativelystable to hydrolysis by NDMs, KPC-3 and OXA-23. The Kcat (i.e., the enzyme turnover rate) ofcefiderocol with IMP-1, VIM-2 and L1 was0.92 s-1, 1.0 s-1 and 12 s-1, respectively, andwas found to be four- to sevenfold lower thanthat of meropenem. The Km (i.e., the enzymeaffinity) of cefiderocol to IMP-1, VIM-2 and L1was 190 mcM, 200 mcM and 510 mcM, respec-tively, compared to meropenem that demon-strated a 58- to 83-fold higher affinity for themetallo-b-lactamases. The catalytic efficiency(Kcat/Km), (i.e., the rate of enzyme–substrateturnover versus the affinity of the enzyme andsubstrate) for cefiderocol against metallo-b-lactamases (L1, VIM-2, and IMP-1) was 260- to417-fold lower than that for meropenem, andthe lowest among all antibacterials tested. Theaffinity (Km) of cefiderocol to KPC-3 and OXA-23 enzymes was shown to be[1600 mcM and4800 mcM, respectively, suggesting weak bind-ing of cefiderocol to these enzymes. Compara-tively, the Km of meropenem to KPC-3 andOXA-23 was 6.5 mcM and 0.028 mcM, respec-tively, suggesting 250- to 100,000-fold higheraffinity of these enzymes for meropenem

20 Infect Dis Ther (2020) 9:17–40

Table1

Invitroactivity

ofcefiderocol,meropenem

,ceftazidim

e/avibactam

andceftolozane/tazobactam

againstEnterobacteralesandnon-ferm

enting

Gram-

negative

bacilli,adapted

from

references

[12,

13]

Organism

(no.

ofisolates)

Antim

icrobial

N.American

isolates

Europ

eanisolates

Com

bined/worldwideisolates

MIC

50MIC

90Range

MIC

50MIC

90Range

MIC

50MIC

90Range

Enterobacterales,all

(6013)

Cefiderocol

0.12

0.5

B0.002–

128

0.25

1B

0.002–

8

MER

B0.06

B0.06

B0.06

to[

64B

0.06

0.12

B0.06

to[

64

CAZ/A

VI

0.12

0.5

B0.06–3

20.25

0.5

B0.06

to[

64

TOL/T

AZ

0.25

1B

0.06

to

[64

0.25

8B

0.06

to[

64

MER-resistant

(246)

Cefiderocol

14

0.008–

8

MER

16[

642to

[64

CAZ/A

VI

1[

640.12

to[

64

TOL/T

AZ

[64

[64

0.25

to[

64

CAZ/A

VI-resistant(57)

Cefiderocol

14

0.12–8

MER

32[

64B

0.06

to[

64

CAZ/A

VI

[64

[64

16to

[64

TOL/T

AZ

[64

[64

0.12

to[

64

TOL/T

AZ-resistant

(597)

Cefiderocol

12

0.008–

128

MER

0.12

64B

0.06

to[

64

CAZ/A

VI

18

B0.06

to[

64

TOL/T

AZ

32[

644to

[64

K.pneum

oniae,all(1528)

Cefiderocol

0.12

0.5

B0.002–

40.25

2B

0.002–

2

MER

B0.06

B0.06

B0.06

to

[64

B0.06

16B

0.06

to[

64

CAZ/A

VI

0.12

0.5

B0.06

to8

0.25

1B

0.06

to[

64

TOL/T

AZ

0.25

1B

0.06

to

[64

0.5

[64

B0.06

to[

64

Infect Dis Ther (2020) 9:17–40 21

Table1

continued

Organism

(no.

ofisolates)

Antim

icrobial

N.American

isolates

Europ

eanisolates

Com

bined/worldwideisolates

MIC

50MIC

90Range

MIC

50MIC

90Range

MIC

50MIC

90Range

MER-resistant

(165)

Cefiderocol

14

0.015–

4

MER

16[

642to

[64

CAZ/A

VI

1[

640.25

to[

64

TOL/T

AZ

[64

[64

1to

[64

E.coli(1830)

Cefiderocol

0.12

0.5

B0.002to

40.12

1B

0.002–

8

MER

B0.06

B0.06

B0.06

to16

B0.06

B0.06

B0.06

to[

64

CAZ/A

VI

0.12

0.25

B0.06–8

0.12

0.25

B0.06

to[

64

TOL/T

AZ

0.25

0.5

B0.06

to

[64

0.25

0.5

B0.06

to[

64

E.cloacae

(594)

Cefiderocol

0.25

10.008–

128

0.5

1B

0.002to

4

MER

B0.06

0.12

B0.06

to32

B0.06

0.12

B0.06

to64

CAZ/A

VI

0.25

1B

0.06

to8

0.25

1B

0.06

to[

64

TOL/T

AZ

0.25

160.12

to[

640.5

16B

0.06

to[

64

E.aerogenes(244)

Cefiderocol

0.12

0.5

0.004to

20.12

0.5

B0.002to

4

MER

B0.06

0.12

B0.06

to16

B0.06

0.12

B0.06

to4

CAZ/A

VI

0.25

0.5

B0.06

to8

0.25

1B

0.06

to8

TOL/T

AZ

0.25

4B

0.06

to32

0.5

8B

0.06

to[64

C.freundii(252)

Cefiderocol

0.12

10.004–

40.12

1B

0.002to

8

MER

B0.06

B0.06

B0.06

to16

B0.06

B0.06

B0.06

to16

CAZ/A

VI

0.12

0.5

B0.06

to8

0.25

1B

0.06

to[

64

TOL/T

AZ

0.25

8B

0.06

to[

640.25

160.12

to[

64

22 Infect Dis Ther (2020) 9:17–40

Table1

continued

Organism

(no.

ofisolates)

Antim

icrobial

N.American

isolates

Europ

eanisolates

Com

bined/worldwideisolates

MIC

50MIC

90Range

MIC

50MIC

90Range

MIC

50MIC

90Range

C.koseri(169)

Cefiderocol

0.5

10.015to

80.5

0.5

0.12

to1

MER

B0.06

B0.06

B0.06

0.5

16B

0.06

to[

64

CAZ/A

VI

0.12

0.25

B0.06

to0.5

0.12

0.25

B0.06

to4

TOL/T

AZ

0.25

0.5

B0.06

to1

0.25

0.5

B0.06

to16

S.marcescens(776)

Cefiderocol

0.12

0.5

0.015–

320.12

0.5

0.015–

2

MER

B0.06

0.12

B0.06

to[

64B

0.06

0.12

B0.06

to[

64

CAZ/A

VI

0.25

0.5

B0.06–1

60.25

0.5

B0.06

to[

64

TOL/T

AZ

0.5

10.12

to[

640.5

10.12

to[

64

A.b

aumannii,all(837)

Cefiderocol

0.25

20.008to[256

0.25

2B

0.002to

[256

MER

8[64

B0.06

to[

6464

[64

B0.06

to[

64

CAZ/A

VI

8[64

0.5to[

6432

[64

B0.06

to[

64

TOL/T

AZ

4[64

B0.06

to[

6416

[64

B0.06

to[

64

MER-resistant

(558)

Cefiderocol

0.5

2B

0.002to

[256

MER

64[

644to[

64

CAZ/A

VI

64[

641to[

64

TOL/T

AZ

32[

641to[

64

MDR(368)

Cefiderocol

0.25

80.015to[

256

MER

64[

64\

0.06

to[

64

CAZ/A

VI

32[

64B

0.06

to[

64

TOL/T

AZ

32[

640.5to[

64

Infect Dis Ther (2020) 9:17–40 23

Table1

continued

Organism

(no.

ofisolates)

Antim

icrobial

N.American

isolates

Europ

eanisolates

Com

bined/worldwideisolates

MIC

50MIC

90Range

MIC

50MIC

90Range

MIC

50MIC

90Range

P.aeruginosa,all(1540)

Cefiderocol

0.12

0.5

B0.002to

40.12

0.5

B0.002to

8

MER

0.5

8B

0.06

to[

640.5

16B

0.06

to[

64

CAZ/A

VI

28

0.12

to[

642

16B

0.06

to[

64

TOL/T

AZ

0.5

2B

0.06

to[

640.5

8B

0.06

to[

64

MER-resistant

(395)

Cefiderocol

0.25

1B

0.002to

8

MER

8[

644to[

64

CAZ/A

VI

464

0.25

to[

64

TOL/T

AZ

1[

640.25

to[

64

CAZ/A

VI-resistant(280)

Cefiderocol

0.25

1–2

0.008–

32

MER

64[

640.12

to[

64

CAZ/A

VI

32[

6416

to[

64

TOL/T

AZ

[64

[64

0.5to[

64

TOL/T

AZ-resistant

(310)

Cefiderocol

0.25

1–2

0.004–

32

MER

64[

640.12

to[

64

CAZ/A

VI

32[

641to[

64

TOL/T

AZ

[64

[64

0.5to[

64

MDR(262)

Cefiderocol

0.25

1B

0.002–

32

MER

32[

64B

0.06

to[

64

CAZ/A

VI

32[

640.5to[

64

TOL/T

AZ

[64

[64

0.5to[

64

24 Infect Dis Ther (2020) 9:17–40

Table1

continued

Organism

(no.

ofisolates)

Antim

icrobial

N.American

isolates

Europ

eanisolates

Com

bined/worldwideisolates

MIC

50MIC

90Range

MIC

50MIC

90Range

MIC

50MIC

90Range

S.maltophilia(340)

Cefiderocol

0.12

0.5

0.004–

640.12

0.25

B0.002–

64

MER

[64

[64

0.25

to[

64[

64[

640.5to[

64

CAZ/A

VI

1664

0.5to[

6416

640.5to[

64

TOL/T

AZ

16[64

0.25

to[

6416

[64

0.25

to[

64

B.cepacia

complex

(93)

Cefiderocol

0.015

0.12

B0.002–

320.015

0.5

B0.002–

32

MER

48

0.12–3

24

161–

64

CAZ/A

VI

48

0.5–

324

80.25–3

2

TOL/T

AZ

432

0.25

to[

642

320.25

to[

64

MER-resistant

[31]

Cefiderocol

0.06

8B

0.002–

32

MER

8162

8–64

CAZ/A

VI

48

0.25–3

2

TOL/T

AZ

432

0.5to[

64

MERmeropenem

,CAZ/AVIceftazidim

e/avibactam,TOL/TAZ

ceftolozane/tazobactam

,MIC50

minim

umconcentration(m

g/L)to

inhibitgrow

thof

50%

ofisolates,M

IC90

minim

umconcentration(m

g/L)to

inhibitgrow

thof

90%

ofisolates

Infect Dis Ther (2020) 9:17–40 25

compared to cefiderocol. Steady-state kineticsdemonstrated 3–10 times lower hydrolysisvelocity of cefiderocol with NDM-1 comparedto meropenem, ceftazidime and cefepime [16].Cefiderocol has also demonstrated low-levelhydrolysis by the IMP-type metallo-carbapene-mases, IMP-1 and IMP-6, the latter of which canconfer imipenem-susceptible, meropenem-re-sistant phenotypes to Enterobacterales strains[17]. Against Ambler class-D carbapenemases,OXA-48, OXA-23, and OXA-40, cefiderocolmaintained full susceptibility with no changesto the MIC compared to aminopenicillins andcarboxypenicillins that demonstrated high-level resistance, and imipenem that demon-strated intermediate-level resistance in E. coliisolates modified with blaOXA-48, blaOXA-23 andblaOXA-40 genes [18].

In addition to carbapenemases, cefiderocolhas also demonstrated stability and low induc-tion potential against chromosomal Amp-C b-lactamases. In an in vitro assessment of cefide-rocol activity, stability and propensity for AmpC induction in P. aeruginosa and Enterobactercloacae, MICs for ceftazidime, cefepime andaztreonam in AmpC-producing isolates wereC 16-fold higher than the parental strains,whereas MICs for cefiderocol were B 4-fold dif-ferent. AmpC enzyme affinities for cefiderocolin P. aeruginosa were 40- and 17-fold lower thanfor ceftazidime and cefepime, respectively. In E.cloacae, enzyme affinities were[940- and[8-fold lower for cefiderocol than for ceftazidimeand cefepime, respectively. Double disc diffu-sion assays performed to detect the propensityfor ampC induction of cefiderocol compared toimipenem demonstrated that cefiderocol didnot induce ampC b-lactamases in P. aeruginosaor E. cloacae [19].

Mutations causing alteration or loss of porinchannels, such as in OmpK35-36 in K. pneumo-niae, do not appear to significantly impact thein vitro activity of cefiderocol [11, 16, 17].Additionally, P. aeruginosa PAO1 strains with atransposon insertion in oprD leading to porinloss demonstrated only a twofold increase incefiderocol MIC (0.25 lg/mL) over the parentstrain compared to an eightfold increase inimipenem MIC (8 lg/mL). On the other hand,two- to fourfold lower MICs in P. aeruginosa

strains without functional mexB or oprM genessuggest that cefiderocol may be a substrate ofthe MexAB-OprM efflux pump [11]. However,overproduction of these efflux pumps onlyslightly increased MICs, suggesting a limitedeffect an efflux pump mechanism on the activ-ity of cefiderocol. MICs to cefiderocol against P.aeruginosa strains with over-expression of theMexAB-OprM efflux pump were only twofoldhigher than the PAO1 parent strain, as opposedto ceftazidime, aztreonam and ciprofloxacinthat demonstrated fourfold higher MICs [11].In vitro frequency of resistance analyses in P.aeruginosa PAO1 strains have demonstratedlower mutational frequencies with cefiderocol(2.9 9 10-8 and\7.1 9 10-9 colonies perinoculum) compared to ceftazidime (3.1 9 10-7

and 3.4 9 10-7 colonies per inoculum), at4-times and 10-times the MIC, respectively.Whole genome sequencing identified muta-tions in the promoter regions of pvdS, whichincreases pyoverdine production, and fecl,which increases expression of the FecA OMPiron transporter, leading to a fourfold increasein cefiderocol MICs and suggesting that thesemutations may contribute to cefiderocol resis-tance in P. aeruginosa [20].

Limited data suggest poor activity of cefide-rocol against aerobic Gram-positive organismsand anaerobes, both Gram-positive and Gram-negative. Cefiderocol has demonstrated signifi-cantly higher MICs to most aerobic Gram-posi-tive organisms compared topiperacillin/tazobactam, cefepime, and mer-openem except for Streptococcus pneumoniaeATCC 49619 and Streptococcus pyogenes ATCC10389, which demonstrated MICs of 2 and 1 lg/mL, respectively. However, activity of cefidero-col against these strains of Streptococci werestill weaker than other b-lactams tested. Foranaerobic organisms, although cefiderocol hasdemonstrated some in vitro activity againststrains of Bacteroides spp., Prevotella spp., andClostridium spp., consistency has not beenobserved across multiple clinical isolates and itis less potent compared to meropenem andmetronidazole [11].

26 Infect Dis Ther (2020) 9:17–40

PHARMACOKINETICSAND PHARMACODYNAMICS

Cefiderocol appears to display linear pharma-cokinetics, as examined in phase I and II stud-ies. At steady-state, cefiderocol 2 g given as a60-min infusion every 8 h in healthy adultsachieved a peak serum concentration (Cmax) of153 lg/mL, elimination half-life (t�) of 2.72 h,and systemic clearance (Cl) of 3.89 L/h(Table 2). Cefiderocol is predominantly excretedunchanged via the kidneys [21].

Cefiderocol was also examined in 38 indi-viduals with varying degrees of renal impair-ment (mild, moderate, or severe and end-stagerenal disease (ESRD) requiring hemodialysis).Ratios of AUC0–inf in mild, moderate, severerenal impairment and ESRD compared to nor-mal renal function were 1, 1.5, 2.5, and 4.1,respectively. This is indicative that cefiderocolexposure increases as renal function decreases.Patients with ESRD requiring hemodialysis hada mean drug clearance of 3.1 L/h with approx-imately 60% of the dose removed byhemodialysis. Plasma protein binding rangedfrom 53% to 65% and was similar betweengroups [22]. In a population pharmacokineticanalysis of healthy patients and patients withcomplicated urinary tract infection (cUTI) oracute uncomplicated pyelonephritis (AUP),cefiderocol pharmacokinetics were best descri-bed by a three-compartment model [23]. Effectsof disease state on clearance and volume wereobserved with infected patients having 26%higher total clearance and 36% higher centralcompartment volume of distribution comparedto healthy patients.

Similar to other cephalosporins, the phar-macokinetic/pharmacodynamic (PK/PD) indexthat best predicts activity is percentage of a 24-htime period that the unbound drug concentra-tion exceeds the MIC (fT[MIC) [24–27]. Vari-ous dosing regimens were tested in murinethigh and lung infection models caused byGram-negative bacteria, including E. coli, K.pneumoniae, P. aeruginosa, A. baumannii, and S.maltophilia. Mean % fT[MIC for a 1 log10reduction was 73.3% for Enterobacterales and77.2% for P. aeruginosa in thigh infection

models. In lung infection models, the mean %fT[MIC for Enterobacterales, P. aeruginosa, A.baumannii, and S. maltophilia were 64.4%,70.3%, 88.1%, and 53.9%, respectively [27].Ghazi et al. characterized cefiderocol PK/PD in aneutropenic murine thigh infection model.MICs in this study were determined by brothmicrodilution, using iron-depleted medium tomimic the environment of acute infection.Eight clinical isolates of P. aeruginosa with MICsranging from 0.063 to 0.5 lg/mL were used inthis study. Targets for bacteriostasis, 1 log10, and2log10 reductions in bacteria were observed atmean % fT[MIC of 76.3, 81.9, and 88.2,respectively [28]. Based on these animal infec-tion models, a % fT[MIC of 75% was selectedas the target for cefiderocol [25, 26].

Monte Carlo simulations based on thepharmacokinetics observed in patients withcUTI or AUP revealed that the fT[MIC valueswere[75% in all patients at the dose admin-istered in this study. Patients with normal renalfunction received 2-g doses as a 1-h infusionevery 8 h and doses were adjusted for renaldysfunction. Furthermore, Katsube et al. createda pharmacokinetic model in patients with var-ious degrees of renal function to determine theprobability of target attainment (PTA) for fT[MIC. In patients with normal renal function, a2-g dose given as a 3-h infusion every 8 hresulted in[90% PTA for 75% fT[MIC for anMIC B 4 lg/mL. All dose-adjusted regimens forpatients with renal impairment also met thesecriteria. Sensitivity analyses were performedevaluating PTA for 100% fT[MIC and greaterthan 90% was still met for MIC B 4 lg/mL. Inpatients with augmented renal function(CrCl C 120 mL/min), a more frequent dosesuch as 2 g every 6 h may be necessary. Ascefiderocol is removed by hemodialysis, a sup-plemental dose after intermittent hemodialysisshould be considered to provide[90% of PTA[29]. Table 3 shows the recommended renaldose adjustments from the package insert,which are based on this study [30].

The intrapulmonary pharmacokinetics ofcefiderocol was evaluated in a phase I, single-center, open-label study in 20 healthy adultmales. Each subject underwent one bron-choscopy in order to calculate cefiderocol

Infect Dis Ther (2020) 9:17–40 27

Table2

Pharmacokineticsof

cefiderocola[21,

23]

Doseb

nDem

ograph

ics

CrC

l

(mL/m

in)

Cmax

(lg/mL)

t max(h)c

AUC

(lg�h/mL)

Vss(L)

t �(h)

Cl(L/h)

Feu(%

)Fu

(8h)

1g9

16

Health

yadultmales,

meanage

28.8years,mean

BMI22.7kg/m

2

147.5±

20.1d

76.4

(4.6)

1.0(1.0–1

.0)

168.1(11.8)

e2.26

(5.8)

5.95

(7.0)

68.3

(4.1)

1gq8h

9 10days

8Health

yadultmales,

meanage

32.6years,mean

BMI22.89kg/m

2

141.5±

22.6d

69.8

(13.3)

1.0(1.0–1

.0)

160.5(13.5)

f2.35

(18.5)

6.23

(13.5)

70.0

(6.1)

1gq8h

9 10days

8Health

yadultmales,

meanage

29.6years,mean

BMI21.9kg/m

2

130.6±

17.1d

72.2

(11.5)

1.0(1.0–1

.25)

168.6(11.0)

f2.19

(4.3)

5.93

(11.0)

64.7

(12.8)

2g9

16

Health

yadults,m

ean

age30.5years,

meanBMI

21.42kg/m

2

131.3±

29.6d

156(7.9)

1.0(1.0–1

.0)

389.7(9.0)e

2.74

(10.2)

5.13

(9.0)

61.5

(10.6)

2gq8h

9 10days

8Health

yadultmales,

meanage

34.1years,mean

BMI22.39kg/m

2

133.5±

23.0d

153(12.9)

1.0(1.0–1

.25)

366.5(14.0)

f2.72

(21.6)

5.46

(14.0)

71.4

(5.3)

1g9

18

Health

yadults,m

ean

age56.5,m

ean

BMI27.3kg/m

2

100.5

(76.4–

122.3)

81.0

(27.4)

1.0(1.0–1

.0)

213.4(26.5)

e13.5

(30.2)

2.8(16.5)

4.7(26.5)

68.6

(17.3)

0.44

(9.8)

1g9

18

Health

yadults,m

ild

renalim

pairment,

meanage58.1,

meanBMI

30.9kg/m

2

78.2 (67.3–

91.5)

73.4

(21.3)

1.0(1.0–1

.0)

218.7(22.2)

e14.8

(17.7)

3.0(8.4)

4.6(22.2)

68.3

(14.0)

0.42

(19.1)

28 Infect Dis Ther (2020) 9:17–40

Table2

continued

Doseb

nDem

ograph

ics

CrC

l

(mL/m

in)

Cmax

(lg/mL)

t max(h)c

AUC

(lg�h/mL)

Vss(L)

t �(h)

Cl(L/h)

Feu(%

)Fu

(8h)

1g9

18

Health

yadults,

moderaterenal

impairment,mean

age60.1,m

ean

BMI29.4kg/m

2

55.3 (38.6–

79.3)

78.0

(31.1)

1.0(1.0–1

.0)

312.3(38.4)

e15.4

(28.7)

4.1(12.6)

3.2(38.4)

55.5

(19.6)

0.45

(18.5)

1g9

16

Health

yadults,severe

renalim

pairment,

meanage51.8,

meanBMI

29.4kg/m

2

27.7 (15.6–

39.1)

80.1

(19.8)

1.0(1.0–1

.0)

543.2(23.6)

e16.4

(23.4)

6.9(30.6)

1.8(23.6)

0.44

(10.1)

1g9

18

Health

yadults,

ESR

D,m

eanage

45.8,m

eanBMI

30.9kg/m

2

ESR

Dwithout

HD

11.7

(6.0–2

3.1)

93.0

(27.8)

1.0(1.0–1

.0)

880.7(24.2)

e14.2

(22.5)

9.6(33.4)

1.1(24.2)

0.37

(27.0)

1g9

18

Health

yadults,

ESR

D,m

eanage

45.8,m

eanBMI

30.9kg/m

2

ESR

Don

HD

75.4

(31.1)

1.0(1.0–1

.5)

318.1(20.3)

e26.6

(33.5)

9.5(32.8)

3.1(20.3)

0.42

(21.5)

Infect Dis Ther (2020) 9:17–40 29

Table2

continued

Doseb

nDem

ograph

ics

CrC

l

(mL/m

in)

Cmax

(lg/mL)

t max(h)c

AUC

(lg�h/mL)

Vss(L)

t �(h)

Cl(L/h)

Feu(%

)Fu

(8h)

0.75

g

q6h

3Adults

withcU

TIor

AUP,

meanage

60.5,m

eanweight

77.8kg

83.0

±31.9d

69.3

(67.3–

72.6)g

1003

(872.9–1

181)

g,h

1gq6h

4079.9

(30.7–

122)

g1026

(316.4–1

686)

g,h

1.5gq6h

8102(73.8–

138)

862.0(525.2–1

227)

1gq8h

2287.5

(57.0–

161)

1108

(588.4–1

719)

1.5gq8h

26134(79.0–

292)

1186

(588.2–2

505)

2gq8h

139

138(29.5–

460)

1184

(270.0–3

562)

CrClcreatinine

clearance,Cmaxmaxim

umplasmaconcentration,

t maxtimeto

Cmax,A

UCarea

underthecurve,Vssvolumeof

distribution

understeady-state

cond

itions,t

�term

inalhalf-life

elim

ination,

Cltotaldrug

clearance,Feufraction

ofexcreted

dose

unchangedin

theurine,Fu

fraction

oftotaldrug

that

isun

boun

din

plasma

aValuesexpressedas

geom

etricmean(%

coefficient

ofvariation)

forallparametersun

lessspecified

bInfusionsgivenover

60min

cValuesexpressedas

median(range)

dValuesexpressedas

mean±

standard

deviation

eAUC

from

0to

?fAUC

from

0to

sgValuesexpressedas

mean(range)

hDailyAUC

30 Infect Dis Ther (2020) 9:17–40

concentrations in the plasma, epithelial liningfluid (ELF), and alveolar macrophages (AM).Cefiderocol was administered as a single 2 ginfusion over 60 min. ELF concentrationsappear to parallel plasma concentrations, indi-cating rapid distribution from plasma to ELF.The geometric mean ELF concentration ofcefiderocol was 13.8, 6.69, 2.78, and 1.38 mg/Lat 1, 2, 4, and 6 h from the start of infusion. TheAUC ratios in ELF to total plasma were 0.101and 0.239 to free plasma, suggesting * 24%penetration into the ELF. AUC ratios in AMs tototal plasma and free plasma were 0.0177 and0.0419, respectively, suggesting much lowerpenetration into AMs [31]. Future work is nee-ded to assess intrapulmonary penetration ininfected patients, particularly those who arecritically ill.

Drug–drug interaction potentials of cefide-rocol were assessed in an open-label, random-ized, crossover study of 3 study cohorts. Cohort1 assessed the effect of cefiderocol on fur-osemide, an OAT1 and OAT3 substrate. Cohort2 assessed metformin, an OCT1, OCT2, andMATE2-K substrate, and cohort 3 evaluatedrosuvastatin, an OATP1B3 substrate.

Furosemide and metformin exposures were notimpacted by cefiderocol co-administration.Slight increases in rosuvastatin concentrationswere observed with ratios of maximum plasmaconcentration and area under the plasma con-centration–time curve of 1.28 and 1.21, respec-tively, when co-administered with cefiderocol[32].

ANIMAL EFFICACY MODELS

Cefiderocol has been studied in a variety ofanimal models to determine its clinical roleagainst Gram-negative organisms. Cefiderocolhumanized exposures (2 g every 8 h as a 3-hinfusion) for 24 h was evaluated in a neu-tropenic murine thigh model. Isolates studiedwere P. aeruginosa (n = 21), A. baumannii(n = 35), and Enterobacterales (n = 39) withcefiderocol MIC ranges from 0.12 to[ 256 mg/L. For isolates with MIC B 4 mg/L, bacterialstasis or C 1 log10 of bacterial kill was achievedin 85% of P. aeruginosa isolates, 88% of A. bau-mannii isolates, and 77% of Enterobacteralesisolates. In 28 isolates with MIC C 8 mg/L, thissame observation only occurred in 2 strains.Bacterial-density studies using a subset of 15Gram-negative isolates comparing cefiderocol,meropenem, and cefepime activities were alsoconducted. Even in isolates with high-levelcefepime (MICs up to[ 512 mg/L) or mer-openem (MICs up to[512 mg/L) resistance,cefiderocol was efficacious against all isolates.Cefiderocol bacterial reduction was 2.6 ± 0.5and 2.1 ± 0.9 log10 CFU against cefepime- andmeropenem-susceptible isolates, respectively,and was similar to those of cefepime (2.6 ± 0.5log10 CFU) and meropenem (2.2 ± 0.6 log10CFU). Mean bacterial kill of cefiderocol againstcefepime- and meropenem-resistant isolates was1.5 ± 0.4 log10 CFU [33].

The efficacy of cefiderocol against car-bapenem-resistant Gram-negative bacilli wasexamined in immunocompetent-rat respiratorytract infection models [34]. Six total isolateswere evaluated: 1 cephalosporin-susceptible P.aeruginosa isolate, 1 multidrug-resistant P.aeruginosa isolate, 2 multidrug-resistant A. bau-mannii isolates, and 2 carbapenem-resistant K.

Table 3 Cefiderocol Dose regimens based on renal func-tion [30]

Renal function Doseregimena

Augmented (CG-CLCR, C 120 mL/min) 2 g q6h

Normal (CG-CLCR, 90 to\ 120 mL/min) 2 g q8h

Mild impairment (CG-CLCR, 60

to\ 90 mL/min)

2 g q8h

Moderate impairment (CG-CLCR, 30

to\ 60 mL/min)

1.5 g q8h

Severe impairment (CG-CLCR, 15

to\ 30 mL/min)

1 g q8h

ESRD (CG-CLCR,\ 15 mL/min) 0.75 g q12h

Intermittent hemodialysis 0.75 g q12h

CG-CLCR creatinine clearance estimated by Cockcroft-Gault equationa All doses given as a 3-h infusion

Infect Dis Ther (2020) 9:17–40 31

pneumoniae isolates. A humanized exposure ofcefiderocol 2 g every 8 h as a 3-h infusion for4 days was compared to a humanized exposureof ceftazidime 1 g every 8 h as a 0.5-h infusionfor 4 days. Cefiderocol resulted in a[3 log10reduction in CFU of all 5 carbapenem-resistantisolates. However, ceftazidime only demon-strated efficacy against the cephalosporin-sus-ceptible P. aeruginosa isolate. Ghazi et al.showed similar results in a neutropenic murinethigh infection model using 8 P. aeruginosaisolates, including ones with resistance to 2preclinical candidate siderophores, cefepimeand levofloxacin. Cefiderocol resulted in[1log10 CFU reduction in all 8 isolates, includingthose with resistance to other siderophores [35].

Stainton et al. evaluated the in vivo efficacyof cefiderocol against 12 Gram-negative isolates(P. aeruginosa, A. baumannii, and Enterobac-terales) in a murine thigh infection model.Cefiderocol MICs ranged from 0.5 to 16 lg/mLwith elevated cefepime, meropenem, cef-tazidime, and/or piperacillin/tazobactam MICs.Cefiderocol, administered at humanized expo-sures of 2 g every 8 h (3 h infusion), was com-pared to untreated control at 24, 48, and 72 h.Sustained kill with cefiderocol exposure over72 h was observed in 9 isolates. It is importantto note that while regrowth did occur in someisolates, the pattern of regrowth in their studywas inconsistent with the emergence of resis-tance observed with other siderophores and thephenomenon of adaptive resistance was notobserved over the 72 h period. In isolates thatwere retested for MICs after cefiderocol expo-sure, only one isolate (1/54 samples, 1.8%)demonstrated an increase in MIC from 1 to4 lg/mL for an E. coli isolate at 72 h [36]. This isnotable as adaptive resistance has been welldocumented in other siderophore compounds.For these compounds, bacterial growth wasobserved to be similar to that in control animalsfollowing supratherapeutic exposure to a side-rophore-conjugated monobactam in P. aerugi-nosa with increases in MIC up to C 16 fold [37].

Although the majority of organisms evalu-ated in these animal studies have been P.aeruginosa, A. baumannii, and Enterobacterales,Takemura et al. conducted an assessment ofcefiderocol against S. maltophilia in a murine

lung infection model. Four clinical isolates wereused in this study with cefiderocol MICs rang-ing from 0.125 to 0.25 lg/mL. Cefiderocoladministration resulted in[ 3 log10 reductionin all isolates. The in vivo efficacies of cefide-rocol were superior to those of ciprofloxacinand at least comparable or superior to those oftigecycline [38].

CLINICAL EFFICACY

The clinical efficacy of cefiderocol has beenevaluated in a phase II study among adultpatients with cUTI or AUP. This was a multi-center, double-blind, parallel-group, random-ized, non-inferiority study comparingcefiderocol to imipenem/cilastatin. Adultpatients with a diagnosis of cUTI or AUP wererandomized 2:1 to receive cefiderocol 2 g every8 h administered over 60 min orimipenem/cilastatin 1 g every 8 h for a durationof 7–14 days. Step-down or switch to oralantibiotics was not permitted in this study. Keyexclusion criteria included baseline urine cul-ture with more than 2 pathogens, fungal uri-nary tract infection, carbapenem-resistantpathogens, and CrCl\20 mL/min [39].

The primary efficacy outcome was a com-posite end point of clinical response andmicrobiological response at the test of cureassessment 5–9 days after the last dose of studymedication. Response was evaluated in themodified intention-to-treat (mITT) population,which included all randomly assigned partici-pants who received at least one dose of studydrug [39].

A total of 448 patients were randomized andreceived at least one dose of the study drug and371 patients with a qualifying Gram-negativeorganism were included in the mITT popula-tion. Baseline demographics were similarbetween groups, with an average age ofapproximately 61 years and 55% female. Over70% of patients in both arms had a diagnosis ofcUTI with or without pyelonephritis, with E. colibeing the most common pathogen isolated(60% in the cefiderocol arm vs. 66% in theimipenem/cilastatin arm). P. aeruginosa wasisolated in 18 (7%) patients in the cefiderocol

32 Infect Dis Ther (2020) 9:17–40

group and 5 (4%) in the imipenem/cilastatingroup [39].

The primary outcome of clinical and micro-biological response was met in 183 (73%) of 252patients in the cefiderocol group and 65 (55%)of 119 patients in the imipenem/cilastatingroup (adjusted treatment difference 18.58%;95% CI 8.23–28.92; p = 0.0004) at test of cure.This met the pre-specified criterion for non-in-feriority. At test of cure, microbiologicalresponse was higher in the cefiderocol groupthan the imipenem/cilastatin group (73% vs.56%; 95% CI 6.92–27.58) with no differences inclinical response (90% vs. 87%; 95% CI - 4.66to 9.44). This study was designed to demon-strate non-inferiority, but a post hoc analysiswas consistent with superiority, with theadjusted treatment difference of 18.58% favor-ing cefiderocol and the lower limit of the CIexceeding zero.

Per-pathogen microbiological outcomeswere also assessed. Treatment differences forpatients with E. coli and K. pneumoniae wereconsistent with that in the mITT population. Inpatients with P. aeruginosa infectious, the pri-mary outcome was met in 7/15 (47%) patientsin the cefiderocol group and 2/4 (50%) patientsin the imipenem/cilastatin group. Compositeclinical and microbiological response rates forESBL producing organisms were consistent withthose for the overall cohort (62.9% vs. 47.2%;difference 16.66, 95% CI - 3.08 to 36.40) [39].

In addition to the published phase II study,multiple phase III trials are currently underwayor awaiting publication of their results. Theseinclude one pneumonia study (NCT03032380),one BSI study (NCT03869437), and one study insevere infections caused by carbapenem-resis-tant Gram-negative pathogens (NCT02714595).Although one study is still enrolling, two of thestudies have been completed with preliminaryresults presented at scientific conferences and/or at the FDA advisory committee meeting.

CREDIBLE-CR (NCT02714595) was a multi-center, randomized, open-label study of cefide-rocol compared to best available therapy (BAT)for the treatment of severe infections caused bycarbapenem-resistant Gram-negative pathogensand was presented to the US FDA as part of theapplication for drug approval [40]. The results

have not yet been presented further at scientificmeetings nor have they undergone peer-re-viewed publication. Disease states includedwere healthcare-associated pneumonia (HCAP),hospital acquired pneumonia (HAP), ventilatorassociated pneumonia (VAP), cUTI, BSI, andsepsis. Cefiderocol 2 g every 8 h was given as a3-h infusion and BAT was chosen by the inves-tigator and consisted of up to 3 antibacterials.The primary outcome was a clinical outcome attest of cure for patients with HAP/VAP/HCAP,BSI/sepsis, and a microbiologic outcome forpatients with cUTI. A total of 101 patients wererandomized to the cefiderocol arm and 49patients to the BAT arm (safety population),with 80 and 38, respectively, having central-laboratory-confirmed infections due to car-bapenem-resistant Gram-negative bacilli. These118 patients made up the CR-mITT populationand were the primary efficacy population.Baseline demographics were similar with amean age of 63 years and APACHE II score of 15.Forty-five percent of patients had APACHE IIscores C 16. The majority of patients had abaseline diagnosis of pneumonia (44.6%cefiderocol vs. 44.9% BAT). While most patientsin the cefiderocol arm received monotherapy(n = 66, 82.5%), the majority of patients in theBAT arm received combination therapy (n = 27,71.1%), largely with colistin-based regimens. Inthe CR-mITT population clinical cure rates attest of cure were comparable between groupsoverall (52.5% cefiderocol vs. 50% BAT) and foreach individual disease state HAP/VAP/HCAP(50% cefiderocol vs. 52.6% BAT), BSI/Sepsis(43.5% vs 42.9%), and cUTI (70.6% vs. 60%).However, all-cause mortality at day 14, day 28,and day 49 was, respectively, numericallyhigher in the cefiderocol group (18.8%, 24.8%,33.7%) compared to BAT (12.2%, 18.4%,20.4%). The mortality imbalance was greatest atdays 14, 28, and 49 for patients with HAP/VAP/HCAP (cefiderocol 24.4%, 31.1%, and 42.2% vs.BAT 13.6%, 18.2%, and 18.2%) and BSI/sepsis(cefiderocol 16.7%, 23.3%, and 36.7% vs. BAT5.9%, 17.6%, 23.5%). The hazards ratio for timeto death with cefiderocol was 1.77, however the95% confidence interval (0.87–3.57) crossed 1,with a p value of 0.11. Concerningly, thegreatest imbalance with deaths at day 49 were

Infect Dis Ther (2020) 9:17–40 33

in patients with A. baumannii [cefiderocol 19/39(49%) vs. BAT 4/17 (24%)], and those withAPACHE II scores C 16 [21/46 (46%) vs. 5/22(23%]. Although numbers were small, concernswere also noted with other non-fermenters. Day49 mortality rates for P. aeruginosa were 6/17(35%) for cefiderocol and 2/12 (17%) for BAT.Further, all five patients in the study with S.maltophilia infections were randomized tocefiderocol with 4 (80%) demonstrating day 49mortality [40].

APEKS-NP (NCT03032380) was a phase III,double-blind, randomized, active-controlled,non-inferiority trial of cefiderocol for the treat-ment of HAP, VAP, or HCAP caused by Gram-negative pathogens. Patients were randomizedto cefiderocol 2 g every 8 h or meropenem 2 gevery 8 h, both as a 3-h infusion. Linezolid wasadministered in both arms for a duration of atleast 5 days and cefiderocol or meropenem for7–14 days [41]. The primary endpoint was all-cause mortality at day 14 for the mITT popula-tion with a non-inferiority margin of 12.5%.Cefiderocol was non-inferior with respect to all-cause mortality to meropenem at day 14 [12.4%vs. 11.6% (difference 0.8%; 95% CI - 6.6 to8.2%)] and day 28 [21.2% vs. 20.1% (difference1.1%; 95% CI - 8.0 to 10.3)]. Mortality was alsosimilar between groups at day 14, day 28, andend of study in the intention-to-treat popula-tion [40].

Real-world clinical use of cefiderocol has alsobeen documented in a few case reports. The firstcase was in a 78-year-old female with extremelydrug-resistant (XDR) P. aeruginosa native aorticvalve endocarditis. This isolate was found toharbor a bla(Vietnam ESBL) gene and susceptible toonly gentamicin, amikacin, and colistin. Thepatient was also found to be rectally colonizedwith OXA-48 K. pneumoniae and OXA-23/OXA-51 A. baumannii. Despite combination therapywith colistin and gentamicin or colistin andmeropenem, the patient was persistently bac-teremic on days 56, 62, and 68, and the decisionwas made to request cefiderocol for compas-sionate use. Blood cultures cleared after 2 daysof cefiderocol therapy, 1 day prior to valve sur-gery. Cefiderocol and colistin combinationtherapy was continued for an additional3 weeks. An episode of transient neutropenia

occurred near the end of therapy, but neu-trophil counts returned to the normal rangewithin a few days of stopping antibiotics [42].Another case of compassionate cefiderocol useoccurred in an adult male patient with XDR A.baumannii (susceptible to colistin) and car-bapenemase-producing K. pneumoniae (suscep-tible to colistin, gentamicin, and ceftazidime/avibactam) BSI and VAP. Cefiderocol was initi-ated on day 35 after persistent fevers andworsening lung infiltrates on various colistin-based combination therapies. After 14 days ofcefiderocol therapy, chest X-rays showed com-plete resolution of lung infiltrates, and thepatient was discharged to a rehabilitationdepartment [43]. Cefiderocol was also used tosuccessfully treat a 46-year-old patient withMDR P. aeruginosa intra-abdominal infectionsusceptible only to amikacin, cefiderocol, col-istin, and gentamicin. After 28 days of cefide-rocol and metronidazole therapy, CT of theabdomen demonstrated complete resolution ofthe intra-abdominal abscess and the patient wasultimately discharged to independent living[44]. Lastly, cefiderocol treatment for 14 weeksresulted in clinical and radiological cure in a15-year-old male with chronic osteomyelitiscaused by XDR P. aeruginosa carrying blaNDM-1

and ESBL K. pnemoniae. Combination therapywith aztreonam and cefiderocol was originallyused, but aztreonam was discontinued after2 weeks due to increasing liver function mark-ers. Intermittent episodes of decreased whitecell count with nadir at 1200/mm3 was notedon cefiderocol therapy and resolved sponta-neously without any adjustments [45].

SAFETY AND TOLERABILITY

The available body of evidence from phase I andphase II studies suggests that cefiderocol is welltolerated and has a safety profile similar to thatof other cephalosporins. In a phase I, dose-as-cending study in 40 patients, no serious orclinically significant adverse events wereobserved. Cefiderocol was administered at dosesof 100–2000 mg in the single-dose study and1–2 g every 8 h in the multiple-dose study. Inthe single-dose study group, 9 adverse events

34 Infect Dis Ther (2020) 9:17–40

were reported in 6/30 (20%) of patients withdiarrhea (2 events in 2 subjects) and rash (2events in 2 subjects) being the most common.In the 10-day multiple-dose study, 22 adverseevents were reported by 16 subjects. Theseincluded alanine aminotransferase (ALT) levelincrease (n = 4), aspartate aminotransferase(AST) level increase (n = 4), creatine phosphok-inase increase (n = 3), white blood cell increase(n = 2), rash (n = 2), and one case each of diar-rhea, pyrexia, abdominal pain, headache,oropharyngeal pain, and urine positive forwhite blood cells. Allergy tests were conductedfor the two participants who reported rash inthe 2000-mg group. Levels were almost withinnormal ranges and measurement of cefiderocol-specific immunoglobulin G and immunoglob-ulin E showed nondetectable levels. One par-ticipant in the multiple-dose group withdrewdue to pyrexia [21].

In the second phase I trial, safety and toler-ability of cefiderocol was assessed in 30 partici-pants with varying levels of renal impairment.No serious adverse events or deaths werereported in this study. The most frequentlyreported adverse event was contact dermatitis(7.9%), which were assessed as unrelated to thestudy drug. Drug-related adverse events werenoted in 5 patients (13.2%), including nausea,maculopapular rash, urticaria, myalgia, andpolyuria. There was no correlation between theincidence of adverse events and the degree ofrenal impairment. One patient discontinuedtreatment due to urticaria [22].

Adverse events in the phase II cUTI or AUPstudy were similar between the cefiderocol andimipenem/cilastatin groups (41% vs. 51%).Treatment emergent adverse events were alsosimilar (9% vs. 11%). Adverse events withrates[2% in the cefiderocol group were diar-rhea (4%), hypertension (4%), constipation(3%), and infusion site pain (3%). A total of 14serious adverse events were reported in thecefiderocol group, including 1 case of C. difficilecolitis. One death was reported in the cefidero-col group due to cardiac arrest, although thiswas considered unrelated to the study drug bythe investigator [39].

The rate of adverse events in the CREDIBLE-CR study were similar, with over 90% of

patients in the cefiderocol arm and BAT armexperiencing at least 1 adverse event. The inci-dence of adverse events considered to be treat-ment-related were 14.9% in the cefiderocol armand 22.4% in the BAT arm. The most commonoverall adverse events reported in the cefidero-col arm (C 10%) were diarrhea, increased ALT,increased AST, pleural effusion, and chest pain[40].

The effect of cefiderocol on QT and correctedQT (QTcF) interval was also evaluated in a phaseI study in healthy adult subjects. Cefiderocolwas administered as a 3-h infusion in normaldoses of 2 g and supratherapeutic doses of 3 gand 4 g compared to moxifloxacin 400 mg asthe positive control. No clinically significanteffect was found on the QTcF interval or otherECG parameters with any cefiderocol dose.Moxifloxacin resulted in a prolongation of theQTcF interval for all time points [46].

To summarize, the limited data availablefrom phase I and phase II studies have notdemonstrated significant safety concerns forcefiderocol; however publication of the phaseIII data have yet to occur. Further studies willneed to be conducted to comprehensively assessdrug–drug interactions. It is also unclear if thereis a significant cross-reactivity between peni-cillins or cephalosporins and cefiderocol. Whilecefiderocol does not appear to share a similarside with any penicillins, it shares the same R1side chain with aztreonam and ceftazidime anda similar R2 side chain with cefepime [47].

CONCLUSION AND PLACEIN THERAPY

Cefiderocol is a first-in-class siderophorecephalosporin with broad coverage againstmany drug-resistant Gram-negative bacteria. Itsunique mechanism of action allows for highintracellular penetration into the periplasmicspace and increased stability to many b-lacta-mases, including both serine-type (KPC, OXA)and Ambler class B metallo-b-lactamases (VIM,IMP, NDM). Additionally, due to its ability topenetrate the cells by mechanisms independentof classic porin channels, cefiderocol mayremain active when b-lactam resistance is

Infect Dis Ther (2020) 9:17–40 35

driven by porin channel mutations. Data fromglobal surveillance studies demonstrate potentin vitro activity against a wide variety of Gram-negative pathogens, including P. aeruginosa, A.baumannii, Enterobacterales, and S. maltophilia.

The PK/PD target best associated with effi-cacy for cefiderocol is fT[MIC, similar to othercephalosporins. Cefiderocol is mainly renallyexcreted and requires dose adjustments for bothrenal impairment and augmented renal clear-ance. Based on pharmacodynamic analyses, adosage of 2 g every 8 h as a 3-h infusion wasselected. In vivo efficacy of cefiderocol has beenstudied in various animal models, includingmurine and rat infection models, and has per-formed similarly to or superior to comparatordrugs, such as tigecycline, ciprofloxacin, andcefepime.

Cefiderocol has an important place in ther-apy for cUTI and AUP, particularly in infectionsdue to MDR Gram-negative organisms. Theadverse event profile, low risk of drug interac-tions, and the ability to largely avoid all 3mechanisms of carbapenem resistance in Gram-negative pathogens make cefiderocol animportant antibiotic to have in our armamen-tarium. In the cUTI study, with a primarycomposite endpoint of microbiological eradi-cation and clinical response at test of cure,cefiderocol was non-inferior toimipenem/cilastatin [40]. Outside of the cUTIstudy, clinical data for cefiderocol are limited tophase II and unpublished phase III studies.

The place in therapy of cefiderocol for sys-temic infections such as pneumonia and BSIdue to drug-resistant pathogens remainsunclear. The all-cause mortality imbalance inCREDIBLE-CR study is concerning. Even moreconcerning is that the imbalance was driven bythe very pathogens (A. baumannii, P. aeruginosa,S. maltophilia), disease states (pneumonia, BSI),and patient types (high severity of illness)where cefiderocol is most needed. While it isencouraging that clinical cure rates were similarbetween cefiderocol and BAT, this does notoffset the mortality concerns. Cefiderocol iscoming to market at a time when either RCT orreal-world clinical data are available thatstrongly suggest the superiority of ceftazidime/avibactam, meropenem/vaborbactam,

imipenem/relebactam, ceftolozane/tazobactam,and plazomicin over this same comparator[48–53]. Therefore, the lack of an improvementin clinical cure combined with a signal forpotentially increased mortality is suboptimal.However, it is important to note that CRED-IBLE-CR does represent a different populationthan those in the aforementioned studies, withnearly half the patients having A. baumanniiinfections (compared to zero in the other data-sets such as those studies targeted CRE or P.aeruginosa), and a larger proportion of patientsbeing treated for pneumonia (large proportionsof the CRE trials were BSI or cUTI.) Conversely,there are the high-level results of APEKS-NP, astudy focused on nosocomial pneumonia withan impressive comparator arm of high-dose,extended infusion meropenem. This studydemonstrated no difference between cefiderocoland meropenem with regards to all-cause mor-tality. This increases confidence that the pre-clinical excitement of cefiderocol can hold truein the clinical setting; however, additional de-tails related to these data are needed beforefurther judgment can be made.

So where does this leave the clinician? Giventhe unknowns and concerns, at this point,cefiderocol should not be placed in the samecategory as other novel b-lactam therapies (cef-tazidime/avibactam, ceftolozane/tazobactam,meropenem/vaborbactam, and imipenem/rele-bactam), and these agents should be givenpreferential placement above cefiderocol forresistant pathogens susceptible to both. Oncefurther data become available, it will be appro-priate to revisit this stance, but current evidencedoes not support putting them on equalgrounds. Further, until more data are available,it would be prudent to continue to prefer non-b-lactam options (trimethoprim-sulfamethoxa-zole, tetracyclines, fluoroquinolones) to cefide-rocol for less commonly encountered non-fermenters, such as S. maltophilia andBurkholderia spp. unless resistance or intoler-ance prevents this. In scenarios where there areno good alternatives (e.g., polymyxin-only sus-ceptible pathogens), a firm recommendationcannot be made. Until further data are avail-able, clinicians will need to weigh the risks andbenefits of cefiderocol, and consideration

36 Infect Dis Ther (2020) 9:17–40

should be given to combination therapy. Fullpublication of CREDIBLE-CR and APEKS-NP, aswell as completion of the GAME CHANGER trial(NCT03869437) comparing cefiderocol andstandard therapy for all comer Gram-negativeBSI, will help further place cefiderocol. Addi-tionally, clinicians should be encouraged topublish their real-world experience, both goodand bad, to help inform this decision.

ACKNOWLEDGEMENTS

Funding. No funding or sponsorship wasreceived for this study or publication of thisarticle.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship, takeresponsibility for the integrity of the work as awhole, and have given their approval for thisversion to be published.

Disclosures. Jason M. Pogue has been aconsultant for Shionogi & Co., Ltd (manufac-turer of cefiderocol), Merck, and QPex. Janet Y.Wu and Pavithra Srinivas have nothing todisclose.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any studies with humanparticipants or animals performed by any of theauthors.

Open Access. This article is licensed under aCreative Commons Attribution-NonCommer-cial 4.0 International License, which permitsany non-commercial use, sharing, adaptation,distribution and reproduction in any mediumor format, as long as you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons licence, andindicate if changes were made. The images orother third party material in this article areincluded in the article’s Creative Commonslicence, unless indicated otherwise in a creditline to the material. If material is not included

in the article’s Creative Commons licence andyour intended use is not permitted by statutoryregulation or exceeds the permitted use, youwill need to obtain permission directly from thecopyright holder. To view a copy of this licence,visit http://creativecommons.org/licenses/by-nc/4.0/.

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