A.7 Cefiderocol

Application for inclusion of FETCROJA/FETROJA on WHO EML
Application for inclusion of

FETCROJA/FETROJA (cefiderocol) on the
WHO Model List of Essential Medicines
Submitted to:
WHO Essential Medicines List Secretariat
Expert Committee on the Selection and Use of Essential Medicines
Essential Medicines Team
Medicines Selection, IP and Affordability (MIA)
Department of Health Products Policy and Standards (HPS)
World Health Organization
20 Avenue Appia
CH-1211 Geneva 27
Switzerland
Email: emlsecretariat@who.int
Applicant: Point of Contact:

Shionogi & Co., Ltd. Monika Schneider
1-8, Doshomachi 3-chome, Chuo-ku, Director, Global AMR Policy
Osaka 541-0045, Japan Email: monika.schneider@shionogi.com
Tel : +81-6-6202-2161 Tel: +1-973-936-3275
Date of Submission: November 30, 2020

Contents
List of Tables ............................................................................................................................................. 2
List of Figures ............................................................................................................................................ 2
1. Summary statement of the proposal for inclusion, change or deletion ............................................... 4
2. Relevant WHO technical department and focal point (if applicable) ................................................... 4
3. Name of organization consulted and /or supporting the application .................................................. 4
4. International Nonproprietary Name (INN) and Anatomical Therapeutic Chemical (ATC) code of the
medicine........................................................................................................................................................ 4
5. Dose form(s) and strength(s) proposed for inclusion; including adult and age-appropriate pediatric
dose forms/strengths (if appropriate). ......................................................................................................... 5
6. Whether listing is requested as an individual medicine or as representative of a pharmacological
class ………………………………………………………………………………………………………………………………………………………..5
7. Treatment details (requirements for diagnosis, treatment and monitoring)....................................... 5
Therapeutic dosage regimen of treatment............................................................................................... 5
Reference WHO guidelines and/or other evidence-based clinical guidelines.......................................... 7
Consideration of any additional requirements associated with treatment, such as diagnostics,
specialized treatment facilities, administration, monitoring, etc. ............................................................ 8
8. Information supporting the public health relevance. ........................................................................... 8
Epidemiological information on the burden of antimicrobial resistance ................................................. 8
Assessment of current use ...................................................................................................................... 13
Target population(s) ............................................................................................................................... 13
Likely impact of treatment on the disease ............................................................................................. 13
9. Review of benefits: summary of evidence of comparative effectiveness .............................................. 14
Identification of clinical evidence (search strategy, systematic reviews identified, reasons for
selection/exclusion) ................................................................................................................................ 14
Summary of available data and estimates of comparative effectiveness .............................................. 15
Individual study results (in vitro surveillance outcomes) ................................................................... 15
Clinical study results (clinical outcomes) ............................................................................................ 19
10. Review of harms and toxicity: summary of evidence of safety ............................................................ 27
Estimate of total patient exposure to date............................................................................................. 27
Description of the adverse effects/reactions and estimates of their frequency .................................... 28
Summary of available data (appraisal of quality, summary of results) and summary of comparative
safety against comparators..................................................................................................................... 30
11. Summary of available data on comparative cost and cost-effectiveness ............................................ 31
1
12. Summary of regulatory status and market availability of the medicine .............................................. 32
13. Availability of pharmacopoeia standards (British Pharmacopoeia, International Pharmacopoeia,
United States Pharmacopoeia, European Pharmacopoeia) ....................................................................... 33
14. Comprehensive reference list ............................................................................................................... 34
Appendix A .................................................................................................................................................. 39
List of Tables
Table 1. Administration and dosing of cefiderocol ....................................................................................... 6
Table 2. Prevalence of CR Gram-negative infections in the EU-5 ............................................................... 10
Table 3. Estimated Disease Burden Due to Priority Pathogens in the US (Adapted from AR Threat Report)
.................................................................................................................................................................... 10
Table 4. GRADE quality assessment for the cefiderocol clinical trials ........................................................ 15
Table 5: Percent of isolates with in vitro susceptibility to cefiderocol, colistin, ceftolozane-tazobactam
and ceftazidime-avibactam ......................................................................................................................... 16
Table 6. Breakpoints for non-susceptibility used in definition of DTR (μg/mL).......................................... 17
Table 7. Percent of isolates with in vitro susceptibility to cefiderocol, ceftazidime/avibactam,
ceftolozane/tazobactam and colistin.......................................................................................................... 17
Table 10. Summary of Microbiological and Clinical Outcomes .................................................................. 21
Table 11. Day 14 All-cause Mortality (mITT population) (from Wunderink et. al. (47)) ............................. 23
Table 12. Secondary Endpoints, clinical cure and microbiological eradication at TOC in the mITT (from
Wunderink et. al. (47)) ................................................................................................................................ 24
Table 13. Clinical cure by Clinical Diagnosis and time point (from Bassetti et. al. (48)) ............................. 25
Table 14: All-cause morality in the safety population (from Bassetti et. al. (48)) ...................................... 26
Table 15. Summary of on-going or planned human studies ...................................................................... 27
Table 16. Patients with Treatment Related Adverse Events by System Organ Class and Preferred Term
(All Phase II/III Studies) Safety Population .................................................................................................. 28
Table 17: Cefiderocol availability and pricing ............................................................................................. 32
Table 18. Regulatory status of the technology ........................................................................................... 32
List of Figures
Figure 1: Cefiderocol mechanism of action (from Morgan et. al. (4)) .......................................................... 6
Figure 2. Worldwide carbapenem resistance ............................................................................................... 9
Figure 3. Aggregated resistance rates of A. baumannii to carbapenems, fluoroquinolones or ceftazidime
.................................................................................................................................................................... 11
Figure 4. Aggregated resistance rates of P. aeruginosa to ceftazidime, fluoroquinolones or carbapenems
.................................................................................................................................................................... 11
2
Figure 5. Aggregated resistance rates of Enterobacter aerogenes/cloacae to fluoroquinolones,

piperacillin-tazobactam, cephalosporins (3rd gen) or carbapenems .......................................................... 12
Figure 6. Aggregated resistance rates of K. pneumoniae to carbapenems, fluoroquinolones,
cephalosporins (3rd gen) or piperacillin-tazobactam .................................................................................. 12
Figure 7. Antibacterial activity against β-lactamase-producing pathogens ............................................... 14
Figure 8. Primary efficacy results: Composite outcome at TOC by predefined subgroups ........................ 20
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1. Summary statement of the proposal for inclusion, change or

deletion
Cefiderocol is being proposed for inclusion in the WHO Model List of Essential Medicines under the
Reserve Group Antibiotics, which includes antibiotics reserved for the treatment of confirmed or
suspected infections due to multi-drug-resistant organisms.
Cefiderocol is a parenteral siderophore cephalosporin antibiotic discovered and developed by Shionogi.

The main feature of cefiderocol is its potent activity against a broad spectrum of Gram-negative
pathogens, including WHO Priority Pathogens carbapenem-resistant Acinetobacter baumannii,
Pseudomonas aeruginosa, and Enterobactericeae (1).
Cefiderocol has received FDA approval for complicated urinary tract infection (cUTI) and hospital-
acquired bacterial pneumonia (HABP)/ventilator-associated bacterial pneumonia (VABP) indications, and
EMA approval for the treatment of infections due to aerobic Gram-negative organisms in adults with
limited treatment options. This latter indication is pathogen focused and supports use in hospitalized
patients with a confirmed or suspected carbapenem-resistant infection and where cefiderocol is the
best option based on pathogen susceptibility information and/or where other treatment choices are
inappropriate. Pathogen-focused prescribing aligns with appropriate use related to diagnostic testing.
Inclusion of cefiderocol on the WHO Model List of Essential Medicines is being requested for the
following reasons:
x Antimicrobial resistance is a growing problem worldwide and patients are in need of novel
antibacterial options
x Cefiderocol offers coverage of multidrug-resistant, Gram-negative pathogens that other listed
antibiotics have no – or limited – activity against
x Cefiderocol has a safety profile consistent with other cephalosporins.
2. Relevant WHO technical department and focal point (if applicable)

The Department of Health Products Policy and Standards and the Global Coordination and Partnership
AMR Department.
3. Name of organization consulted and /or supporting the application

Shionogi & Co., Ltd.
4. International Nonproprietary Name (INN) and Anatomical

Therapeutic Chemical (ATC) code of the medicine
INN: Cefiderocol
ATC: J01D
4
5. Dose form(s) and strength(s) proposed for inclusion; including

adult and age-appropriate pediatric dose forms/strengths (if
appropriate).
Cefiderocol is supplied as a white to off-white, sterile, lyophilized powder for reconstitution in single-
dose, clear glass vials. Each vial contains cefiderocol sulfate tosylate equivalent to 1 g of cefiderocol. The
powder should be reconstituted with 10 mL of either sodium chloride 9 mg/ml (0.9%) solution for
injection or 5% dextrose injection taken from the 100 mL bags that will be used to prepare the final
infusion solution and should be gently shaken to dissolve. The final volume of the reconstituted solution
in the vial will be approximately 11.2 mL (2, 3).
The recommended dosage of cefiderocol is 2 grams administered every 8 hours by intravenous (IV)
infusion over 3 hours in adults with a creatinine clearance (CLcr) of 60 to 119 mL/min. Dosage
adjustment of cefiderocol is recommended for patients with CLcr less than 60 mL/min, including
patients receiving intermittent hemodialysis or continuous renal replacement therapy, and for patients
with CLcr 120 mL/min or greater. The recommended duration of treatment with cefiderocol is 7 to 14
days. The duration of therapy should be guided by the patient’s clinical status.
Cefiderocol is currently marketed in the United Kingdom (UK) and Germany (as FETCROJA) and the
United States (US) (as FETROJA).
Cefiderocol is currently being investigated in pediatric populations in the US (NCT04215991/EudraCT

2019-002121-30) and the EU (NCT04335539/EudraCT 2019-002120-32). These phase 2 studies will
evaluate the safety, tolerability and PK of cefiderocol in patients who are 3 months to less than 18 years
of age and have Gram-negative bacterial infections or cUTI.
6. Whether listing is requested as an individual medicine or as

representative of a pharmacological class
Cefiderocol is being requested as an individual medicine within the Reserve Group Antibiotics.
7. Treatment details (requirements for diagnosis, treatment and

monitoring)
Therapeutic dosage regimen of treatment
Cefiderocol is a parenteral siderophore cephalosporin antibiotic discovered and developed by Shionogi.
In addition to passive diffusion through outer membrane porin channels (4 in Fig. 1), cefiderocol can
bind to extracellular free iron via its siderophore side chain (1 in Fig. 1), allowing active transport into
the periplasmic space of Gram-negative bacteria through siderophore uptake systems (2 in Fig. 1). This
mechanism allows for higher concentrations of cefiderocol in the bacteria than with passive diffusion
alone and enables entry even with porin channel mutations. Once across the outer membrane, the iron
dissociates (3 in Fig. 1), and cefiderocol subsequently binds to penicillin binding proteins (PBPs),
inhibiting bacterial peptidoglycan cell wall synthesis which leads to cell lysis and death (5 in Fig. 1).
5
Figure 1: Cefiderocol mechanism of action (from Morgan et. al. (4))
Cefiderocol is indicated for the treatment of infections due to aerobic Gram-negative organisms in
adults with limited treatment options in the EU, where it is recommended that cefiderocol should be
used to treat patients that have limited treatment options only after consultation with a physician with
appropriate experience in the management of infectious diseases. The EU label is pathogen-focused,
allowing for flexibility in prescribing for different sites of infection. Combined with diagnostic testing, the
label also supports appropriate use.
In the US, cefiderocol is indicated for adult patients with cUTI or HABP/VABP caused by Escherichia coli,
Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacae complex
or Acinetobacter baumannii complex, Escherichia coli, Enterobacter cloacae complex, Klebsiella
pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens, respectively. Administration and
dosing are described in Table 1.
Table 1. Administration and dosing of cefiderocol

Method of administration Intravenous use; administered by intravenous infusion over 3
hours.
Doses 1 g/vial; the recommended dose for individuals with normal
renal function is 2g over 3h infusion
Dosing frequency Every 8 hours (three times daily) for individuals with normal
renal function
Average length of a course of Overall duration of treatment is in accordance with the site of
treatment infection.
Anticipated average interval Each treatment cycle lasts 8 hours; 3h of infusion and then 5h
between courses of treatments until the next cycle begins.
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Anticipated number of repeat For complicated urinary tract infections including pyelonephritis,
courses of treatments the recommended treatment duration is 5 to 10 days. For
hospital-acquired pneumonia, including ventilator-associated
pneumonia, the recommended treatment duration is 7 to 14
days. Treatment up to 21 days may be required.
Dose adjustments Dose adjustments are necessary for patients with renal
impairment (reduced dose) or augmented renal function
(increased dose).
It is recommended that patients with
x CLcr 30 to 59ml/min be dosed with 1.5g cefiderocol
infused over 3h every 8h
x CLcr 15 to 29mL/min be dosed with 1g cefiderocol
infused for 3h every 8h
x CLcr less than 15mL/min be dosed with 0.75g
cefiderocol infused over 3h every 12h
x CLcr greater than or equal to 120mL/min be dosed with
2.0g cefiderocol infused over 3h every 6h
Reference WHO guidelines and/or other evidence-based clinical guidelines

Clinical guidelines are developed for treatment of bacterial-associated indications based on location of
infection or pathogen type. In many cases, there is not a single standard of care because treatment will
need to be tailored to the type of pathogen. Recommendations refer either to most common infection
sites (e.g. pneumonia, sepsis, cUTI) or, more recently, to pathogen types, e.g., infections with multidrug-
resistant (MDR)/carbapenem-resistant (CR) Gram-negative bacteria (5-8) or more specificly, ESBL-
producing bacteria or CR bacteria (9).
Fewer guidelines refer to specific treatments (10, 11). As clinical data are rare, recommendations are
often based on evidence derived from in vitro susceptibility testing results, case studies, observational
studies and expert opinion, which is standard and the most appropriate approach in antimicrobial
treatment decisions. In general, all guidelines recommend that appropriate treatment should be started
early (within hours) for patients who are vulnerable to infection or with suspected infections, and these
guidelines often support the antibacterial de-escalation strategy and recommend that empirical
antibacterial therapy should be implemented in accordance with local microbiological data and previous
treatment (12).
Cefiderocol is a newly approved antimicrobial drug, so is not yet included on many formal clinical
guidelines. However, its utility against a number of critical pathogens has been recognized by both the
WHO and the Infectious Diseases Society of America (IDSA) (13, 14).
Activity against pathogens on the WHO Priority Pathogen list is one measure of clinical benefit. In the
WHO report, “2019 Antibacterial Agents in Clinical Development,” cefiderocol is identified as a
siderophore cephalosporin that is active against a number of WHO priority pathogens, including
extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae, Klebsiella pneumoniae (K.
pneumoniae) carbapenemase (KPC), and oxacillinase-48 (OXA-48)-producing Enterobacteriaceae (13).
7
Cefiderocol is also active against both MDR Acinetobacter baumannii (A. baumannii) and MDR
Pseudomonas aeruginosa (P. aeruginosa), which is unique amongst antimicrobials in the current
development pipeline. Further, this report noted that cefiderocol is intrinsically more stable to a variety
of β-lactamases than other β-lactam agents.
In September 2020, the IDSA released “Guidance on the Treatment of Antimicrobial Resistant Gram-
Negative Infections”. IDSA Clinical Guidance documents are developed based on a comprehensive (but
not necessarily systematic) review of the available evidence, coupled with the experience of clinical and
research experts on the topic. This guidance serves as an alternative and complement to comprehensive
clinical practice guidelines (15). The IDSA guidance documents are meant to address specific clinical
questions that are not covered by current guidelines. The September guidance focused on the
treatment of infections caused by extended spectrum beta-lactamase (ESBL) Enterobacterales,
carbapenem-resistant Enterobacterales (CRE), and P. aeruginosa with difficult-to-treat resistance (DTR)
(14). In this IDSA guidance, written prior to FDA approval for HABP/VABP, cefiderocol is recommended
as a preferred treatment for:
x Pyelonephritis and cUTIs caused by CRE or DTR-P. aeruginosa

x Infections outside of the urinary tract caused by CRE resistant to both ertapenem and
meropenem, when carbapenemase testing results are either not available or negative and the
patient has recently traveled from an area where metallo-β-lactamases are endemic
o Cefiderocol is an alternative treatment option for infections outside the urinary tract
caused by DTR-P. aeruginosa
x Infections outside of the urinary tract caused by CRE with NDM or other metallo-β-lactamase
production
x Uncomplicated cystitis caused by DTR-P. aeruginosa
Consideration of any additional requirements associated with treatment, such as

diagnostics, specialized treatment facilities, administration, monitoring, etc.
The use of cefiderocol is for hospital use only, and is not expected to require any specialized equipment,
or to demand additional resources beyond the standard ability to store, prepare and administer
intravenous infusion treatments. Susceptibility testing to cefiderocol and standard monitoring
microbiological evaluation tests are also needed, as is current practice with all hospital use antibacterials
in nosocomial infections.
Cefiderocol should be stored in a refrigerator at 2°- 8°C and should be protected from light. Chemical,
microbiological and physical in-use stability after dilution has been demonstrated for 6 hours at 25°C
and for 24 hours at 2 to 8°C protected from light, followed by 6 hours at 25°C.
8. Information supporting the public health relevance.

Epidemiological information on the burden of antimicrobial resistance
Antimicrobial resistance (AMR) is a major, and growing, threat to global public health. Treatment of
pathogens has become more and more challenging due to the emergence of resistance, especially to
8
carbapenems which are usually reserved for use where other options have failed (1, 16-21). AMR is
estimated to contribute to 700,000 deaths every year globally (22-24). If significant action is not taken, it
is estimated that 10 million lives will be lost each year to AMR by 2050 (22). The WHO has identified CR
A. baumannii, CR P. aeruginosa, and CR, ESBL-producing Enterobacteriaceae as the most critical
pathogens in need of new antibiotics (1).
Gram-negative pathogens are challenging to treat due to their potential intrinsic resistance to
antibacterials and the emergence of acquired resistance, including metallo- and serine β-lactamase
production, porin channel mutations, and efflux pump mechanisms (16). Non-fermenters such as P.
aeruginosa, A. baumannii, and S. maltophilia, are often resistant to a large number of antibacterial
treatments and also differ in their pathogenic potential and transmissibility (25).
Nosocomial infections primarily occur in vulnerable hospitalized patients. These patients are often over
50 years of age, likely to be severely ill, and generally have multiple comorbidities (26, 27). Infections
caused by MDR pathogens, including Gram-negative organisms, can occur at many sites including the
urinary tract, lungs, bloodstream, and abdominal tract.
The rate of infections caused by MDR bacteria continues to increase and limit the utility of existing
antibacterial agents. Reports on CR isolates are highly heterogeneous across the globe (Figure 2), but
the prevalence of carbapenem resistance has been found to be particularly high in Mediterranean
countries, South America and Asia-Pacific countries, with the exception of Japan (28, 29).
Figure 2. Worldwide carbapenem resistance
Source: CDC 2013(24); ECDC 2017(21); Mendes et al.(30); Kiratisin et al.(31)
In its 2018 surveillance report, the European Centre for Disease Prevention and Control (ECDC) reported
an increase in resistance to currently available treatments across some Gram-negative pathogens
between 2015 and 2018 (32). ECDC estimate that nearly 700,000 infections and 33,000 deaths in the EU
and European Economic Area (EEA) in 2015 are a consequence of MDR bacterial infections (23). CR in P.
aeruginosa, K. pneumoniae and Acinetobacter spp. contributed significantly to the number of estimated
9
deaths (in total approximately 9,000 deaths). Across the EU-5 countries (France, Germany, Italy, Spain,
United Kingdom), prevalence of CR Gram-negative infections ranges between 0.14 per 100,000 in the UK
to 3.05 per 100,000 in Italy (Table 2) (23). While there appears to be geographical variation in different
types of carbapenemases, a recent surveillance study reports an overall increase in these enzymes (29,
33).
Table 2. Prevalence of CR Gram-negative infections in the EU-5

Prevalence The United States (US) experiences more than 2.8
EU-5 Country
(Cases/100,000) million antibiotic-resistant infections each year,
France 1.20 resulting in over 35,000 deaths (34). In their 2019
Germany 0.31 Antibiotic Resistant Threat Report, the US Centers
Italy 3.05
for Disease Control and Prevention (CDC)
Spain 0.64
described the prevalence of several priority
United Kingdom 0.14
EU-5 Average 1.07 pathogens in the US (Table 3).
Table 3. Estimated Disease Burden Due to Priority Pathogens in the US (Adapted from AR Threat Report)
Estimated Estimated
Resistant bacteria Source of data
infections deaths
Drug-resistant Neisseria
550,000 N/A All infections
gonorrhoeae
Incident hospitalized Positive clinical cultures,
ESBL-producing Enterobacteriaceae 197,400 9,100
including hospital- & community-onset
Erythromycin-resistant group A
5,400 450 Invasive infections
Streptococcus
Carbapenem-resistant Incident hospitalized positive clinical cultures,
13,100 1,100
Enterobacteriaceae including hospital- & community-onset
Carbapenem-resistant Incident hospitalized positive clinical cultures,
8,500 700
Acinetobacter including hospital- & community-onset
Incident hospitalized positive clinical cultures,
Vancomycin-resistant Enterococcus 54,500 5,400
including hospital- & community-onset
Multidrug-resistant Pseudomonas Incident hospitalized positive clinical cultures,
32,600 2,700
aeruginosa including hospital- & community-onset
Methicillin-resistant Staphylococcus Incident hospitalized positive clinical cultures,
323,700 10,600
aureus including hospital- & community-onset
Drug-resistant Tuberculosis 847 62 Cases
Infections requiring hospitalizations or in
Clostridioides difficile 223,900 12,800
already hospitalized patients
Drug-resistant Campylobacter 448,400 70 All infections
Drug-resistant nontyphoidal
212,500 70 All infections
Salmonella
Drug-resistant Salmonella Serotype
4,100 <5 All infections
Typhi
Drug-resistant Shigella 77,000 <5 All infections
Drug-resistant Streptococcus
900,000 3,600 All infections
pneumoniae
Clindamycin-resistant group B
13,000 720 Invasive infections
Streptococcus
10
Comprehensive epidemiology data are incomplete in many nations where surveillance infrastructure is
lacking. Using a compilation of sources, the Center for Disease Dynamics, Economics & Policy has
created estimates of AMR rates world-wide (35). Figures 3-6 show the estimated percent of resistant
isolates occurring in Asian, Latin American, Middle Eastern and African countries. Broad resistance of A.
baumanni, P. aeruginosa, Enterobacteriaceae, and K. pneumoniae isolates to standard antibiotic
treatments is evident throughout these regions.
Figure 3. Aggregated resistance rates of A. baumanniito carbapenems, fluoroquinolones or ceftazidime
Figure 4. Aggregated resistance rates of P. aeruginosato ceftazidime, fluoroquinolones or carbapenems
11
Figure 5. Aggregated resistance rates of Enterobacter aerogenes/cloac

ae to fluoroquinolones,
piperacillin-tazobactam, cephalosporins (3rd gen) or carbapenems
Figure 6. Aggregated resistance rates of K. pneumoniae to carbapenems, fluoroquinolones,

cephalosporins (3rd gen) or piperacillin-tazobactam
12
Assessment of current use

Cefiderocol is commercially available in the UK, Germany and US. Prior to marketing, cefiderocol was
studied in over 700 patients through clinical studies.
In addition to experience in clinical trials and post-approval patient access, compassionate use programs
have been in place since 2016. Approximately 300 requests for cefiderocol have been received through
these programs and 184 have been granted product. While the compassionate use program ended in
the US upon -commercial availability of cefiderocol, cefiderocol is still provided through compassionate
use programs in Europe, the Asia Pacific region and Canada (Special Access Programme) for qualified
patients who have limited treatment options and are not eligible for a clinical trial. The criteria for
compassionate use of cefiderocol were highly restrictive and cefiderocol was used in patients with
serious infections, most often due to CR non-fermenters, and with limited or no alternative options.
Target population(s)
In Europe, cefiderocol is branded as “FETCROJA” and the indication is: “Fetcroja is indicated for the
treatment of infections due to aerobic Gram-negative organisms in adults with limited treatment
options.”(3) This indication is pathogen focused, not restricted to any specific site of infection.
In the United States, cefiderocol is branded as “FETROJA” and approved for the treatment of cUTI and for
the treatment of HABP and VABP. The “Indications” section of the FDA label is copied here (2):
x FETROJA is indicated in patients 18 years of age or older for the treatment of complicated urinary
tract infections (cUTIs), including pyelonephritis caused by the following susceptible Gram-negative
microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas
aeruginosa, and Enterobacter cloacae complex
x FETROJA is indicated in patients 18 years of age or older for the treatment of hospital-acquired
bacterial pneumonia and ventilator-associated bacterial pneumonia, caused by the following
susceptible Gram-negative microorganisms: Acinetobacter baumannii complex, Escherichia coli,
Enterobacter cloacae complex, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia
marcescens
Likely impact of treatment on the disease

Treatment options for infections with MDR/CR aerobic Gram-negative pathogens are very limited. For
patients with limited treatment options, cefiderocol is the only antimicrobial with demonstrated in vitro
activity against a broad set of pathogens such as CR A. baumannii, CR P. aeruginosa, S. maltophilia, and
CR Enterobacteriaceae (Figure 7) (36, 37). As a result, cefiderocol is estimated to provide better predicted
susceptibility rates and projected clinical success rates with a safety profile consistent with other
cephalosporins.
13
Figure 7. ŶƚŝďĂĐƚĞƌŝĂůĂĐƚŝǀŝƚǇĂŐĂŝŶƐƚɴ
-lactamase-producing pathogens
*Color-coding based on the pathogen susceptibility: Green – Activity reported, yellow – undetermined activity
reported, and red – no clinically relevant activity reported. Source: Thalhammer F, 2018 (38), Theuretzbacher, 2019
(39)
9. Review of benefits: summary of evidence of comparative

effectiveness
Identification of clinical evidence (search strategy, systematic reviews identified, reasons
for selection/exclusion)
To identify all relevant studies for cefiderocol and comparators, a comprehensive systematic literature
review was conducted comprising in vitro and in vivo studies, as well as any comparative or non-
comparative studies and registered clinical trials (RCTs) (including cross-over RCTs); 153 records were
included in the reference set. Full search details are included in Appendix A.
The comparative evidence included in this application were derived from in vitro surveillance studies
and RCTs. As has been discussed in several publications, it is unethical to include in antibiotic clinical
trials patients with infections that are known to be resistant to the comparator treatment, necessitating
a non-inferiority design (40-43). In addition, antibiotic products may face challenges with enrollment
and evidence analysis because (44, 45):
x Immediate treatment is necessary for serious bacterial diseases, so patients may receive
antibiotic therapy before trial enrollment, potentially obscuring the effect of the experimental
antibiotic.
x There may be diagnostic uncertainty with respect to the aetiology of the patients’ underlying
disease, including pathogen identification.
x There may be a need for concomitant antibacterial drug therapy with a spectrum of activity that
may overlap with the antibacterial drug being studied.
x MDR/CR pathogens are still relatively rare in individual hospitals, so a trial to evaluate specific
types of resistance would require the screening and recruitment of a prohibitively large number
of people.
x A comparison of efficacy against all relevant comparators can only be obtained from in vitro
surveillance studies.
Despite these challenges, cefiderocol was demonstrated to have in vitro activity against a number of
MDR and CR pathogens, including those found on the WHO Priority Pathogen list: CR A. baumannii, CR
14
P. aeruginosa, and MDR Enterobactericeae. Cefiderocol was also found to be non-inferior to

imipenem/cilastatin in the treatment of cUTI; non-inferior to high-dose, prolonged infusion (2g
administered over 3hr) meropenem for treatment of HABP/VABP; and an effective treatment against
infections caused by a broad set of aerobic, CR Gram-negative pathogens (46-48).
Each clinical study used its own comparator and was conducted in different patient populations. For this
reason, no overall results summary table is shown here. However, a recent systematic review and meta-
analysis compared the efficacy and safety of new antibiotics to carbapenems for the treatment of cUTI.
The pooled efficacy estimates of composite cure favored the new antibiotics, including cefiderocol, over
carbapenem, and found that new antibiotics were superior to carbapenems in microbiological response
(49).
The quality of the two randomized, controlled, double-blinded studies (APEKS-cUTI and APEKS-NP) and
the randomized, open-label, non-inferential study (CREDIBLE-CR) was assessed to demonstrate the
efficacy and safety profiles. Using the GRADE assessment system, the analysis concluded that the APEKS
studies were of high quality with low risk of bias and the CREDIBLE-CR study was of moderate quality
(Table 4).
Table 4. GRADE quality assessment for the cefiderocol clinical trials
-CR
Summary of available data and estimates of comparative effectiveness

Individual study results (in vitro surveillance outcomes)
The in vitro activity of cefiderocol was studied in large-scale, multinational surveillance and small,
independent national studies (50). The following section describes the multinational surveillance analyses,
SIDERO-WT and SIDERO-CR.
1a) SIDERO-WT results for all Gram-negative isolates (50-52)
The SIDERO-WT analysis (study report S-649266-EB-344-N) was an extensive effort to determine activity
of cefiderocol and relevant comparators against cabapenem-susceptible and carbapenem-resistant
pathogens. Cefiderocol MICs were determined and compared to a panel of relevant antibacterials using
breakpoints from the Clinical & Laboratory Standards Institute (CLSI) (37, 50-53). The cefiderocol MIC of
4µg/mL was consistent with the CLSI breakpoints published in 2019 and those derived from PK/PD and
PK analyses in clinical studies. However, subsequently published European Committee on Antimicrobial
Susceptibility Testing (EUCAST) breakpoints for cefiderocol are lower, set as 2mg/L for Enterobacterales
15
and Pseudomonas aeruginosa and not determined for Acinetobacter spp (54). FDA lists breakpoints for
cefiderocol as ≤4µg/mL for Enterobacteriaceae and ≤1µg/mL for P. aeruginosa and A. baumannii
complex (55). Within the SIDERO studies, using the lower FDA and EUCAST breakpoints results in some
isolates shifting from cefiderocol-susceptible to resistant (56). In the clinical context, these lower
breakpoints may have negative consequences for the care of patients with multidrug resistant
infections, which may be incorrectly labeled as resistant to cefiderocol.
Cefiderocol demonstrated activity against the majority of Gram-negative isolates tested at MIC of <4
µg/mL (only MIC90 for B. multivorans was 32 µg/mL) and had higher coverage rates than other examined
comparators (50). To date, 30,459 samples have been tested, with testing of 9,205 Gram-negative
bacterial clinical isolates in 2014–2015, 8,954 in 2015–2016, and 10,470 in 2016–2017 (50). Cefiderocol
was effective at low MICs for more than 99% of isolates in each testing period (50). The latest
surveillance SIDERO-WT study (2016-2017) showed that cefiderocol demonstrated activity against
99.45% of Gram-negative pathogens at MIC of 4µg/mL compared to 90.2% for ceftazidime-avibactam,
84.28% for ceftolozane-tazobactam, and 95.49% for colistin (Table 5) (51).
Table 5: Percent of isolates with in vitro susceptibility to cefiderocol, colistin, ceftolozane-tazobactam

and ceftazidime-avibactam
Polymyxin E Ceftolozane/ Ceftazidime/

Organism Cefiderocol
(colistin) tazobactam avibactam
All Gram-negative 95.49b

99.45 84.28 90.20
(n=30,459) (n=25372)
Enterobacteriaceae 96.54c
99.86 91.43 99.23
(n=20,949) (n=16026)
Non-fermentersa 93.67d
98.53 68.52 70.33
(n=9,510) (n=9346)
CR Enterobacteriaceae
75.55c
(n=654) 98.16 8.40 77.67
(n=581)
(MEPM MIC ≥ 2 µg/mL)
CR Non-fermenters (n=4,331) 86.85d
97.57 34.61 40.96
(MEPM MIC ≥ 4 µg/mL) (n=4208)
CR P. aeruginosa (n=1,154)
99.91 98.35 76.08 75.38
CR A. Baumannii (n=1,891)
94.87 85.14 7.77 16.23
S. maltophilia
99.82 78.17 34.27 42.88
(n=1,173)
Source: (51). MEPM - meropenem; MIC - minimum inhibitory concentration. Green: More than 80% susceptible;
yellow: between 60-80% susceptible, red: less than 60% susceptible. Data reflect all tested clinical strains (SIDERO-
WT-2014/2015/2016 and Proteeae). Ratios (%) susceptible strains were calculated by using the following MIC
criteria: Cefiderocol MIC ≤4 μg/mL, ceftazidime/avibactam MIC ≤8 μg/mL, ceftolozane/tazobactam MIC ≤2 μg/mL
for Enterobacteriaceae, ≤4 μg/mL for non-fermenters, colistin MIC ≤2 μg/mL.
a
Non-fermenters include P. aeruginosa, S. maltophilia, Burkholderia spp, and Acinetobacter spp.
16
b
Burkholderia spp, Proteeae and Serratia spp. were excluded because they are intrinsically resistant to
Polymyxin E (Colistin)
c
Serratia spp. and Proteeae was excluded.
d
Burkholderia spp was excluded.
1b) SIDERO-WT-based analysis of difficult-to-treat resistant (DTR) pathogens (57)
A subsequent analysis focused on a DTR subset of pathogens, which were non-susceptible to

fluoroquinolones, extended-spectrum cephalosporins, and carbapenems (57). The results from this
analysis showed that cefiderocol demonstrated potent activity against DTR Gram-negative pathogens.
Pathogens were defined as DTR if they were non-susceptible to fluoroquinolones (ciprofloxacin),
extended-spectrum cephalosporins (cefepime) and carbapenems (meropenem) according to CLSI M100-
E28:2018 breakpoints (Table 6). Stenotrophomonas maltophilia was considered inherently non-
susceptible to carbapenems, however, an arbitrary breakpoint of >4 μg/mL was used. Among 30,459
Gram-negative isolates collected between 2014 and 2017, 9.3% were non-susceptible to cefepime,
ciprofloxacin and meropenem and could be defined as DTR.
Table 6. Breakpoints for non-ƐƵƐĐĞƉƚŝďŝůŝƚǇƵƐĞĚŝŶĚĞĨŝŶŝƚŝŽŶŽĨ
The DTR phenotype was most frequently observed in Acinetobacter spp. (55.5%), followed by
Burkholderia spp. (19%), Pseudomonas aeruginosa (9.5%) and Enterobacterales (2.7%). Cefiderocol
demonstrated activity in 94.5% of DTR A. baumannii, 99.8% of P. aeruginosa and 98.3% of
Enterobacterales (58). These pathogens were less susceptible to other available treatments (Table 7)
(58).

ceftolozane/tazobactam and colistin
Ceftazidime / Ceftolozane /
Pathogen Cefiderocola Colistina
avibactama tazobactama
DTR Enterobacterales
98.3 78.2 2.05 68.2
(n=573)
DTR P. aeruginosa
99.8 49.5 48.8 98.3
(n=470)
DTR A. baumannii
94.5 14.2 5.8 85
(N=3,451)
17
In addition, 98.7% of carbapenem-non-susceptible (CarbNS) Enterobacteriaceae, and 96.4% of CarbNS

non-fermenters were found to be sensitive to cefiderocol at a MIC of ≤4μg/mL (Table 8).

CarbNSb
98.7 81.3 11.1 71d
Enterobacteriaceae (225)
CarbNSb non-fermentersc
96.4 39.8 37.0 91.5e
(n=1427)
CarbNSb P. aeruginosa
100 75.6 77.3 97.3
(n=406)
CarbNSb A. baumannii
91 11.0 9.0 90.8
(n=565)
S. maltophilia
100 38.8 31.4 86
(n=405)
CarbNS, carbapenem-non-susceptible
a
Ratios (%) susceptible strains were calculated by using the following MIC criteria: Cefiderocol MIC ≤4 μg/mL,
ceftazidime/avibactam MIC ≤8 μg/mL, ceftolozane/tazobactam MIC ≤2 μg/mL for Enterobacteriaceae, ≤4 μg/mL
for non-fermenters, colistin MIC ≤2 μg/mL.
b
CR strain was defined as meropenem MIC ≥2 μg/mL for Enterobacteriaceae, ≥4 μg/mL for non-fermenters
c
Non-fermenters include P. aeruginosa, S. maltophilia, Burkholderia spp, and Acinetobacter spp.
d
Serratia spp. and Proteeae were excluded.
e
Burkholderia spp. was excluded.
Source: Tsuji 2019(51)
2) SIDERO-CR-2014-2016 study (protocol S-649266-EF-115-N)
The SIDERO-CR-2014-2016 study (protocol S-649266-EF-115-N) collected CR isolates and MDR non-
fermenters from Europe, North America, South America, and the Asia-Pacific region. Cefiderocol
demonstrated potent in vitro activity against all of these pathogens (36).
In this study, cefiderocol had in vitro activity at a MIC90 between 0.25 - 8µg/mL against CR
Enterobacteriaceae and MDR non-fermenters (defined as resistant to carbapenems, fluoroquinolones,
and aminoglycosides) (36, 50). For MIC of ≤ 4µg/mL, cefiderocol was active against 96.2% of these
pathogens, which was a higher efficacy than other available treatments (36, 50). Cefiderocol inhibited
the growth of 97.0% of CR Enterobacteriaceae, 99.2% of MDR P. aeruginosa, 90.9% of MDR A. baumanii
and 100% of S. maltophila isolates at a concentration of 4µg/mL (Table 9) (36, 50).
18

CarbNSb
Enterobacteriaceae 97.0 77.0 1.7 77.8c
(n=1022)
MDR P. aeruginosa
99.2 36.3 24.1 99.6
(n=262)
MDR A. baumannii
90.9 NA NA 94.6
(n=368)
S. maltophilia
100 NA NA NA
(n=217)
CarbNS, carbapenem-non-susceptible; MDR, multi drug resistant; NA, susceptibility breakpoints not available
a Ratios (%) susceptible strains were calculated by using the following MIC criteria: Cefiderocol MIC ≤4 μg/mL, ceftazidime/avibactam
MIC ≤8 μg/mL, ceftolozane/tazobactam MIC ≤2 μg/mL for Enterobacteriaceae, ≤4 μg/mL for non-fermenters, colistin MIC ≤2 μg/mL.
b CR strain was defined as meropenem MIC ≥2 μg/mL for Enterobacteriaceae, ≥4 μg/mL for non-fermenters
c Includes 39 Serratia species that are intrinsically resistant to colistin
Source: Hackel, 2018 (36); Yamano (50)
In addition to the high activity of cefiderocol against different drug-resistant species, the SIDERO-CR
study showed that cefiderocol had activity against isolates with previously characterized resistance
factors, including VIM-, NDM-, KPC-, and OXA-producing Enterobacteriaceae, VIM-producing P.
aeruginosa, MEPM-non-susceptible but acquired β-lactamase negative P. aeruginosa, OXA-23 and OXA-
24/40 carbapenemase-producing A. baumannii.
Clinical study results (clinical outcomes)

In addition to in vitro studies, a number of clinical studies were conducted to demonstrate the efficacy
and safety of cefiderocol in patients with bacterial infections. Three phase 2 and phase 3 studies will be
discussed here: APEKS-cUTI, APEKS-NP and CREDIBLE-CR (46-48).
APEKS-cUTI
APEKS-cUTI was a Phase 2, multi-center (multinational), double-blind, randomized, active-controlled,

parallel-group study conducted in hospitalized adult subjects with cUTIs with or without pyelonephritis
or acute uncomplicated pyelonephritis caused by Gram-negative pathogens. This study assessed the
efficacy and safety of intravenous cefiderocol (2g over 3hr every 8 hr) in comparison with intravenous,
high-dose (2g over 3hr every 8 hr) imipenem/cilastatin (IPM/CS) and included 452 patients diagnosed
with complicated urinary tract infections (46) (Clinicaltrials.gov Record NCT02321800).
The primary efficacy endpoint was the composite of clinical outcome and microbiological outcome at
test of cure (TOC). The response rate for the primary efficacy endpoint was 73% (183/252) of patients in
the cefiderocol group and 55% (65/119) of patients in the IPM/CS group (Figure 8). Cefiderocol met the
criteria to demonstrate noninferiority with a prespecified 20% margin. Similar results were observed in
19
the sensitivity analysis (composite clinical and microbiological response in microbiologically-evaluable

(ME) population) (46, 59). Results of this study are detailed in Lancet Infectious Diseases (46).
At TOC, clinical response was 89.7% (226/252) of patients in the cefiderocol group and 87.4% (104/119)
of patients in the IPM/CS group. At follow up, sustained clinical response was higher in the cefiderocol
group (81.3% [205/252] of patients) than in the IPM/CS group (72.3% [86/119] of patients), with an
adjusted treatment difference of 9.02% (95% CI; -0.37%, 18.41%) (Table 10).
Figure 8. Primary efficacy results: Composite outcome at TOC by predefined subgroups
Portsmouth et. al. (46). mITT= modified intention-to-treat. Dotted lines represent prespecified non-inferiority
margins at -20% and -15%.
20
Table 10. Summary of Microbiological and Clinical Outcomes

per Subject by Time Point (from Portsmouth et. al. (46))
The microbiological eradication
rate in the modified intention-
to-treat (mITT) population was
significantly higher at TOC in
the cefiderocol group (73.0%
[184/252] of patients)
compared with the IPM/CS
group (56.3% [67/119] of
patients). The adjusted
treatment difference of 17.25%
(95% CI; 6.92%, 27.58%) in
favor of the cefiderocol group
was statistically significant and
clinically meaningful. Results
for both treatment groups
were similar at early
assessment (EA) and at end of
treatment (EOT). The sustained
microbiological eradication rate
at follow up (FUP) was also
higher in the cefiderocol group
(57.1% [144/252] of patients)
compared with the IPM/CS
group (43.7% [52/119] of
patients). The adjusted
treatment difference of 13.92%
(95% CI; 3.21%, 24.63%) in
favor of the cefiderocol group
was statistically significant and
clinically meaningful.
No new infections were noted

during the study. Superinfection, defined as an uropathogen emerging during study drug therapy, was
limited to a single occurrence of E. coli in one patient (Subject 143-002) in the cefiderocol group. The
patient had E. coli isolated from the urine at the EA visit. Of note, this patient only had P. aeruginosa
isolated at baseline and was treated for 10 days with cefiderocol. The E. coli superinfection was sensitive
to levofloxacin, cefepime, and IPM, and the MIC for cefiderocol was 0.12 μg/mL. Both E. coli and P.
aeruginosa were eradicated at TOC, and P. aeruginosa alone was isolated at FUP.
21
APEKS-NP study
The APEKS-NP study was a multi-center, double-blind, randomized, phase 3 clinical study comparing
cefiderocol with high-dose (HD), extended-infusion meropenem for the treatment of HABP, VABP or
HCABP caused by Gram-negative pathogens. The dose of meropenem was increased from the usual
dose of 1 g to 2 g and extended to a 3-hour infusion to optimize the antibacterial activity of meropenem,
at the request of regulators (60). Cefiderocol demonstrated non-inferiority to HD extended-infusion
meropenem with regard to all-cause mortality at Day 14. Full study results were published in The Lancet
Infectious Disease (47).
Of the 292 patients in the mITT population, 251 (86%) had a qualifying baseline Gram-negative
pathogen, including K. pneumoniae (92 [32%]), P. aeruginosa (48 [16%]), A. baumannii (47 [16%]),
and Escherichia coli (41 [14%]). One hundred forty-two (49%) patients had an APACHE II score of 16 or
more, 175 (60%) were mechanically ventilated, and 199 (68%) were in intensive care units at the time of
randomization. The all-cause mortality rate was 12.4% (18/145 subjects) for the cefiderocol group and
11.6% (17/146 subjects) for the high-dose (HD) meropenem group, demonstrating the noninferiority of
cefiderocol, as the upper limit of the 95% CI was < 12.5% (95% CI: −6.6, 8.2) (Table 11).
Rates of microbiological eradication and clinical cure at TOC aligned with the primary outcome in that
results were similar between the treatments (Table 12). The microbiological eradication at TOC was
47.6% (59/124) in the cefiderocol group and 48.0% (61/127) in the HD meropenem group, and the
clinical cure at TOC was 64.8% (94/145) in the cefiderocol group and 66.7% (98/147) in the HD
meropenem group.
22
Table 11. Day 14 All-cause Mortality (mITT population) (from Wunderink et. al. (47))
23
Table 12.
Secondary Endpoints, clinical cure and microbiological eradication at TOC in the mITT (from
Wunderink et. al. (47))
CREDIBLE-CR
CREDIBLE-CR was a small, randomized, open-label study conducted to evaluate efficacy of cefiderocol
and best available therapy (BAT) in patients with confirmed CR infections. This study was designed as a
descriptive study without hypothesis testing. No formal analysis was planned for any outcomes, and the
analysis described below is descriptive. Patients with nosocomial pneumonia, BSI/sepsis, or cUTI were
included in the study. Most of these patients had severe underlying conditions and ongoing infections
for weeks prior to receiving cefiderocol. CREDIBLE-CR was designed to be observational, with no
inferential analysis to detect differences between the treatment groups for any of the outcomes. A total
of 101 patients received cefiderocol treatment. Cefiderocol demonstrated similar clinical and
microbiological efficacy as BAT in this study (Table 13). Full results of this study have been published
in Lancet Infectious Diseases (48).
24
Table 13. Clinical cure by Clinical Diagnosis and time point (from Bassetti et. al. (48))
The mean age of patients included in this study was 63.1 and 63.0, for cefiderocol and BAT groups,
respectively, though the median age of cefiderocol patients was higher at 69 years versus 62 years in the
BAT group. The mean APACHE II score was 15.3 and 15.4 for cefiderocol and BAT groups, respectively.
Most patients receiving cefiderocol were on monotherapy, while most BAT patients received
combination therapy; 66% of the BAT regimens included colistin. In post-hoc analyses in the safety
25
population, patients in the BAT group received rescue therapy more frequently than those in the
cefiderocol group.
Mortality was assessed during this study, and a mortality imbalance was observed, with numerically
more deaths in the cefiderocol group than the BAT group for patients with pneumonia or BSI, but not
cUTI (Table 14).
While regression analysis did not identify a baseline variable that explained the mortality findings in
CREDIBLE-CR, the mortality imbalance appeared to be driven by Acinetobacter spp. infections. In
subjects with Acinetobacter spp. infection and a history of shock (both shock at baseline and a history of
shock within 31 days of baseline), mortality rates were much higher than in subjects without a history of
shock in both treatment groups (61). The proportion of subjects with a history of shock, or who were in
an ICU at admission, was higher for the cefiderocol group than for the BAT group in subjects with
Acinetobacter spp. infection. These factors imply a higher risk of mortality, and so may provide an
explanation for some of the difference in mortality rates between the treatment groups in the
CREDIBLE-CR study.
Whereas the mortality rate in the cefiderocol group was consistent with previous studies in similar
populations with high levels of A. baumannii infections (62-64), the mortality rate in the BAT group was
substantially lower than expected from previous studies (62-70). The reason for the lower than expected
mortality in the BAT group is not clear but is likely also due to a variety of factors related to baseline
imbalances and other anomalies (such as the low mortality associated with high APACHE II and SOFA
scores). The evidence suggests that the mortality rate in the BAT group was unexpectedly low for the
population randomized and that the mortality in the cefiderocol group was consistent with what has
been reported in previous studies.
Table 14: All-cause mortality in the safety population (from Bassetti et. al. (48))
Compassionate Use and Expanded Access Programs

Since the start of the compassionate use program in 2016, approximately 300 requests have been
received and 184 cases have been granted supply. Patients were included from 12 countries and ranged
in age from 5 months to 84 years. The compassionate use program was suspended in the US post-
26
approval and commercial launch of the drug on February 24, 2020. Details on the compassionate use
program can be found on Clinicaltrials.gov under NCT03780140.
Cefiderocol is still supplied through the compassionate use programs in Europe, the Asia Pacific region
and Canada (Special Access Programme) for qualified patients who have limited treatment options and
are not eligible for a clinical trial. The criteria for compassionate use of cefiderocol are highly restrictive.
It required a life-threatening infection with no alternative treatment options available. If the infection
was sensitive to colistin, compassionate use of cefiderocol was not granted unless colistin was
contraindicated. If established colistin toxicity requiring discontinuation occurred, the patient was
considered eligible for compassionate use.
Over 60% of the patients receiving cefiderocol survived when no other possible treatment options were
available to them (69). None of the observed deaths were considered to be related to cefiderocol (71).
Of those who have completed therapy under the compassionate use program, nine positive outcomes
are published to date (72-80). Cefiderocol has demonstrated a manageable safety profile with the
longest use being more than 90 days in a renal transplant patient where no apparent safety issues were
observed (69).
Shionogi has also supplied cefiderocol to patients in Europe under an Early Access Program. As of
October 2020, 132 patients have been treated under the program, including many with bacterial
infections secondary to COVID-19. Most recently, Falcone et. al. published an interesting case series of
COVID-19 and burn patients, all ventilated and with carbapenem-resistant infections of A. baumannii or
other CR Gram-negative bacteria. These patients had a median APACHE-II score of 37.5 and had been
hospitalized for a median of 23 days prior to infection. All patients were treated with cefiderocol
and after 30 days there was a 90% survival rate with 70% of patients experiencing clinical success (81).
10. Review of harms and toxicity: summary of evidence of safety

Estimate of total patient exposure to date
As of 21 February 2020, 771 subjects have received cefiderocol in clinical studies; this includes 212
healthy subjects (including subjects with renal impairment who were otherwise healthy) in clinical
pharmacology studies, 300 subjects in the APEKS-cUTI study, 148 subjects in the APEKS-NP study, 101
subjects in the CREDIBLE-CR study and 7 subjects in the Phase 1 ELF study. More than 300 patients have
received treatment with cefiderocol under compassionate use and expanded access programs. In
addition, the following studies are on-going or planned (Table 15):
Table 15. Summary of on-going or planned human studies

Type of Study Objectives of the Duration of Study
Subject Population
(Identifier) Study Treatment Status
Phase 2 pediatric study1- Evaluate safety, Part 1: pediatric subjects 3 months to Up to 14 days Ongoing
US (1704R2133) tolerability, and PK < 18 years of age with Gram-negative
bacterial infection
Part 2: pediatric subjects 3 months to
< 18 years of age with cUTI
27
78 to 85 planned subjects, 4:1

randomization
Phase 2 pediatric study1- Evaluate safety, 54 planned pediatric subjects 3 Up to 14 days Ongoing
EU (1802R2135) tolerability, and PK months to < 18 years of age with
Gram-negative bacterial infection
Phase 2 pediatric study 2 (TBD) Evaluate safety, 16 planned pediatric subjects with less Up to 14 days Planned
tolerability, and PK than 3 months of age Gram-negative
bacterial infection
Phase 2 BSI study (GAME CHANGER) Evaluate safety and 284 planned adult subjects with 5-14 days Ongoing
efficacy bloodstream infections (BSI) caused by
Gram-negative pathogens
Cefiderocol is commercially available in the US, UK and Germany; launch in other European countries is
expected in 2021. Cefiderocol was launched in the UK launch was on September 15, 2020, with the
brand name FETCROJA. It launched in the US on February 24, 2020, with the brand name FETROJA.
Description of the adverse effects/reactions and estimates of their frequency

In total across the APEKS-cUTI, APEKS-NP, and CREDIBLE studies, 386 SAEs were reported: 226 SAEs in
subjects who had been treated with cefiderocol, 103 SAEs in subjects who had been treated with
meropenem, 17 SAEs in subjects who had been treated with IPM/CS, and 40 SAEs in subjects who had
been treated with BAT. Table 16 summarizes treatment related adverse events (AEs) for each trial and
for the total patient population studied. In the total sample, 56/549 (10.2%) patients treated with
cefiderocol experienced treatment related AEs and 45/347 (13.0%) patients treated with comparators
experienced treatment related AEs. Overall, there were less treatment emergent AEs with cefiderocol
(344/549 [67.1%]) vs comparators (252/347 [72.6%]). The most common adverse reactions for
cefiderocol were diarrhea (8.2%), constipation (4.6%), pyrexia (4.0%) and UTI (4.7%).
A serious adverse reaction (SAR) is a SAE that is determined by the investigator to have a reasonable
possibility of having been caused by the study medication. In total, 22 SARs were reported: 8 SARs in
patients who had been treated with cefiderocol, 6 SARs in patients who had been treated with
meropenem, 1 SAR in patients who had been treated with IPM/CS, and 7 SARs in patients treated with
BAT.
Table 16. Patients with Treatment Related Adverse Events by System Organ Class and Preferred Term
(All Phase II/III Studies) Safety Population
APEKS-cUTI CREDIBLE-CR Study APEKS NP Study All Studies
Cefiderocol Imipenem/ Cefiderocol BAT Cefiderocol Meropenem Cefiderocol Comparator
System Organ Class N=300 Cilastatin N=101 N=49 n N=148 N=150 N=549 N=347
- Preferred Term n (%) N=148 n (%) (%) n (%) n (%) n (%) n (%)
n (%)
Subjects with any 27 17 15 (14.9) 11 14 (9.5) 17 (11.3) 56 (10.2) 45 (13.0)
Treatment Related AEs (9.0) (11.5) (22.4)
Blood and lymphatic 0 0 0 0 0 2 (1.3) 0 2 (0.6)
system disorders
- Disseminated 0 0 0 0 0 1 (0.7) 0 1 (0.3)
intravascular coagulation
- Thrombocytopenia 0 0 0 0 0 1 (0.7) 0 1 (0.3)
Cardiac disorders 0 1 (0.7) 0 0 0 0 0 1 (0.3)
- Tachycardia 0 1 (0.7) 0 0 0 0 0 1 (0.3)
Ear and labyrinth 0 0 0 0 1 (0.7) 0 1 (0.2) 0
28
disorders
- Ear discomfort 0 0 0 0 1 (0.7) 0 1 (0.2) 0
Gastrointestinal disorders 9 (3.0) 5 (3.4) 4 (4.0) 1 (2.0) 3 (2.0) 5 (3.3) 16 (2.9) 11 (3.2)
- Diarrhoea 4 (1.3) 3 (2.0) 2 (2.0) 0 3 (2.0) 5 (3.3) 9 (1.6) 8 (2.3)
- Nausea 3 (1.0) 1 (0.7) 0 0 0 0 3 (0.5) 1 (0.3)
- Vomiting 1 (0.3) 1 (0.7) 0 1 (2.0) 0 0 1 (0.2) 2 (0.6)
- Abdominal pain upper 1 (0.3) 0 0 0 0 0 1 (0.2) 0
- Ascites 0 0 1 (1.0) 0 0 0 1 (0.2) 0
- Constipation 1 (0.3) 0 0 0 0 0 1 (0.2) 0
- Dry mouth 1 (0.3) 0 0 0 0 0 1 (0.2) 0
- Stomatitis 1 (0.3) 0 0 0 0 0 1 (0.2) 0
- Upper gastrointestinal 0 0 1 (1.0) 0 0 0 1 (0.2) 0
haemorrhage
- Lipoedema 0 1 (0.7) 0 0 0 0 0 1 (0.3)
General disorders 5 (1.7) 0 2 (2.0) 0 0 2 (1.3) 7 (1.3) 2 (0.6)
and administration
site conditions
- Oedema peripheral 2 (0.7) 0 0 0 0 0 2 (0.4) 0
- Infusion site pain 2 (0.7) 0 0 0 0 0 2 (0.4) 0
- Feeling hot 1 (0.3) 0 0 0 0 0 1 (0.2) 0
- Oedema 0 0 1 (1.0) 0 0 0 1 (0.2) 0
- Pyrexia 0 0 1 (1.0) 0 0 0 1 (0.2) 0
- Infusion site erythema 1 (0.3) 0 0 0 0 0 1 (0.2) 0
- Hyperthermia 0 0 0 0 0 1 (0.7) 0 1 (0.3)
- Multiple organ 0 0 0 0 0 1 (0.7) 0 1 (0.3)
dysfunction syndrome
Hepatobiliary disorders 0 1 (0.7) 0 0 1 (0.7) 1 (0.7) 1 (0.2) 2 (0.6)
- Hepatic failure 0 0 0 0 1 (0.7) 0 1 (0.2) 0
- Hepatic function 0 1 (0.7) 0 0 0 0 0 1 (0.3)
abnormal
- Hepatocellular injury 0 0 0 0 0 1 (0.7) 0 1 (0.3)
Immune system 1 (0.3) 0 0 1 (2.0) 0 0 1 (0.2) 1 (0.3)
disorders
- Drug hypersensitivity 1 (0.3) 0 0 0 0 0 1 (0.2) 0
- Anaphylactic reaction 0 0 0 1 (2.0) 0 0 0 1 (0.3)
Infections and 4 (1.3) 6 (4.1) 2 (2.0) 2 (4.1) 3 (2.0) 6 (4.0) 9 (1.6) 14 (4.0)
infestations
- Clostridium difficile 1 (0.3) 4 (2.7) 1 (1.0) 0 0 0 2 (0.4) 4 (1.2)
colitis
- Oral candidiasis 1 (0.3) 0 0 0 1 (0.7) 0 2 (0.4) 0
- Candiduria 2 (0.7) 0 0 0 0 0 2 (0.4) 0
- Clostridium difficile 0 0 0 0 1 (0.7) 2 (1.3) 1 (0.2) 2 (0.6)
infection
- Pseudomembranous 0 0 1 (1.0) 1 (2.0) 0 0 1 (0.2) 1 (0.3)
colitis
- Sepsis 0 0 0 1 (2.0) 1 (0.7) 0 1 (0.2) 1 (0.3)
- Fungal infection 0 1 (0.7) 0 0 0 0 0 1 (0.3)
- Septic shock 0 0 0 1 (2.0) 0 0 0 1 (0.3)
- Systemic candida 0 0 0 0 0 1 (0.7) 0 1 (0.3)
- Vaginal infection 0 1 (0.7) 0 0 0 0 0 1 (0.3)
- Urinary tract infection 0 0 0 0 0 1 (0.7) 0 1 (0.3)
fungal
- Pseudomonas infection 0 0 0 0 0 1 (0.7) 0 1 (0.3)
- Candida infection 0 0 0 0 0 1 (0.7) 0 1 (0.3)
Investigations 5 (1.7) 2 (1.4) 8 (7.9) 2 (4.1) 4 (2.7) 4 (2.7) 17 (3.1) 8 (2.3)
- Alanine 1 (0.3) 0 3 (3.0) 0 2 (1.4) 1 (0.7) 6 (1.1) 1 (0.3)
aminotransferase
increased
- Gamma- 4 (1.3) 1 (0.7) 0 0 2 (1.4) 0 6 (1.1) 1 (0.3)
glutamyltransferase
increased
- Aspartate 0 0 3 (3.0) 0 2 (1.4) 1 (0.7) 5 (0.9) 1 (0.3)
aminotransferase
increased
- Transaminases 0 0 1 (1.0) 0 1 (0.7) 0 2 (0.4) 0
increased
- Liver function test 0 0 2 (2.0) 0 0 0 2 (0.4) 0
29
increased
- Hepatic enzyme 1 (0.3) 0 0 1 (2.0) 0 2 (1.3) 1 (0.2) 3 (0.9)
increased
- Blood creatinine 0 1 (0.7) 1 (1.0) 0 0 0 1 (0.2) 1 (0.3)
increased
- Blood pressure 0 0 1 (1.0) 0 0 0 1 (0.2) 0
increased
- Blood creatine 0 0 0 1 (2.0) 0 0 0 1 (0.3)
increased
- Blood alkaline 0 1 (0.7) 0 0 0 0 0 1 (0.3)
phosphatase increased
Metabolism and nutrition 0 0 1 (1.0) 1 (2.0) 0 0 1 (0.2) 1 (0.3)
disorders
- Hypokalaemia 0 0 1 (1.0) 0 0 0 1 (0.2) 0
- Metabolic acidosis 0 0 0 1 (2.0) 0 0 0 1 (0.3)
Musculoskeletal and 1 (0.3) 0 0 0 0 0 1 (0.2) 0
connective tissue
disorders
- Myalgia 1 (0.3) 0 0 0 0 0 1 (0.2) 0
Nervous system 1 (0.3) 4 (2.7) 1 (1.0) 1 (2.0) 3 (2.0) 0 5 (0.9) 5 (1.4)
disorders
- Dysgeusia 1 (0.3) 1 (0.7) 1 (1.0) 0 0 0 2 (0.4) 1 (0.3)
- Headache 0 3 (2.0) 0 0 1 (0.7) 0 1 (0.2) 3 (0.9)
- Dizziness 0 0 0 0 1 (0.7) 0 1 (0.2) 0
- Paraesthesia 0 0 0 0 1 (0.7) 0 1 (0.2) 0
- Status epilepticus 0 0 0 1 (2.0) 0 0 0 1 (0.3)
Psychiatric disorders 0 0 0 0 1 (0.7) 0 1 (0.2) 0
- Confusional state 0 0 0 0 1 (0.7) 0 1 (0.2) 0
Renal and urinary 0 0 0 5 (10.2) 0 0 0 5 (1.4)
disorders
- Acute kidney injury 0 0 0 4 (8.2) 0 0 0 4 (1.2)
- Renal disorder 0 0 0 1 0 0 0 1 (0.3)
(2.0)
Reproductive system and 0 0 0 0 0 1 (0.7) 0 1 (0.3)
breast disorders
- Vulvovaginal pruritus 0 0 0 0 0 1 (0.7) 0 1 (0.3)
Respiratory, thoracic and 0 0 1 (1.0) 1 2 (1.4) 0 3 (0.5) 1 (0.3)
mediastinal disorders (2.0)
- Pleural effusion 0 0 1 (1.0) 0 1 (0.7) 0 2 (0.4) 0
- Acute respiratory failure 0 0 0 0 1 (0.7) 0 1 (0.2) 0
- Asthma 0 0 0 0 1 (0.7) 0 1 (0.2) 0
- Respiratory arrest 0 0 0 1 0 0 0 1 (0.3)
(2.0)
Skin and subcutaneous 3 (1.0) 0 2 (2.0) 0 2 (1.4) 1 (0.7) 7 (1.3) 1 (0.3)
tissue disorders
- Rash 0 0 1 (1.0) 0 1 (0.7) 0 2 (0.4) 0
- Pruritus 1 (0.3) 0 0 0 0 1 (0.7) 1 (0.2) 1 (0.3)
- Drug eruption 0 0 1 (1.0) 0 0 0 1 (0.2) 0
- Erythema 1 (0.3) 0 0 0 0 0 1 (0.2) 0
- Palmar erythema 0 0 0 0 1 (0.7) 0 1 (0.2) 0
- Rash maculo-papular 1 (0.3) 0 0 0 0 0 1 (0.2) 0
Vascular disorders 0 0 1 (1.0) 0 0 0 1 (0.2) 0
- Hypertension 0 0 1 (1.0) 0 0 0 1 (0.2) 0
Summary of available data (appraisal of quality, summary of results) and summary of

comparative safety against comparators
Overall, cefiderocol was generally well tolerated, and its safety profile was found to be consistent with
that of other cephalosporin antibacterials. The clinical safety for cefiderocol has been investigated in
three randomized clinical trials, two specific to different infection sites and one specific to CR pathogens.
Five hundred and forty-nine patients were treated with cefiderocol in these trails.
30
cUTI study (APEKS-cUTI): The proportion of patients who experienced at least one adverse event (AE)
was lower in the cefiderocol group than in the IPM/CS group (41 % vs 51%). Gastrointestinal disorders,
such as diarrhea and constipation, were the most common adverse events and there was an increased
incidence of C. difficile colitis in the imipenem/cilastatin arm compared with cefiderocol. Serious adverse
events (SAE) occurred in a numerically lower proportion of cefiderocol-treated patients than of IPM/CS-
treated patients (5% vs 8%). The most frequently observed AEs were gastrointestinal, such as diarrhea,
experienced by 4.3% (13/300) and 6.1% (9/148) of cefiderocol- and IPM/CS-treated subjects,
respectively.
HABP/VABP/HCABP study (APEKS-NP): Overall, treatment emergent adverse events (TEAEs) and
treatment-related AEs were balanced between treatment arms. Serious adverse events occurred in 36%
of patients treated with cefiderocol and 30% of patients treated with meropenem. The most frequently
observed AE was urinary tract infection (15.5% in cefiderocol group and 10.7% in meropenem group),
hypokalemia (10.8% in cefiderocol group and 15.3% in meropenem group) and anemia (8.1% in
cefiderocol group and 8% in meropenem group).
CR study (CREDIBLE-CR): The cefiderocol group had a lower incidence of AEs and treatment-related AEs,
but a higher incidence of death, SAEs, and discontinuation due to AEs, compared with BAT. The
incidence of treatment-related AEs leading to discontinuation was similar between treatment groups.
An imbalance in mortality was observed in the cefiderocol arm compared to BAT (18/49 vs 5/25).
Through assessment by the investigator and two independent committees (one blinded), no deaths
were found to be causally associated with cefiderocol. Furthermore, whereas the mortality rate in the
cefiderocol group was consistent with previous studies in similar populations, the evidence suggests that
the mortality rate in the BAT group was unexpectedly low for the randomized population. No single
factor that would explain the imbalance was identified. Small patient numbers and multiple confounders
preclude definitive conclusions.
Like in any other β-lactam antibacterial, patients who have a history of hypersensitivity to carbapenems,
penicillins or other beta-lactam antibacterial medicinal products may also be hypersensitive to
cefiderocol. Before initiating therapy with cefiderocol, careful inquiry should be made concerning
previous hypersensitivity reactions to β-lactam antibacterials.
11. Summary of available data on comparative cost and cost-

effectiveness
Cefiderocol is appropriate for the treatment of infections due to aerobic Gram-negative organisms in
adults with limited treatment options. Treatment options may be limited due to MDR or CR pathogens,
which are associated with higher mortality rates and increased clinical and economic burden. For
critically ill patients at risk of rapid deterioration, where a MDR or CR pathogen is suspected, cefiderocol
can provide broad efficacy requiring no trade-off against possible toxicity. Without definitive evidence
that an infection is resistant to first-line treatment, empiric therapy may be used and appropriate
treatment may be delayed.
A recent systematic review in Chest examined the impact of delayed antibiotic therapy in patients with
severe bacterial infections. The authors found that mortality was significantly lower in patients who did
not experience delay in receiving the appropriate therapy (82). In addition, several systematic reviews
31
examined the impact of AMR and MDR infections on healthcare costs, and all found an association of
increased costs with resistance (83-85). As a result, antibiotics that can effectively treat MDR infections,
like cefiderocol, have the potential to impart both health benefits and healthcare savings.
The wholesale acquisition cost of cefiderocol in the UK and US is shown in Table 17.
Table 17: Cefiderocol availability and pricing

Country Pack size Currency Price to wholesaler
United Kingdom 10 vials GBP £ 1,319.00
United States 10 vials USD $ 1,833.33
The treatment length varies from patient to patient, depending on infection site and underlying patient
conditions; the dose of cefiderocol varies with renal function, but for a normal renal function, the
standard dose is 2g on a 3h infusion, every 8h. This represents a daily dose of 6 vials a day, which is
equivalent to:
- £ 791.4 per day in the UK

- $ 1,099.99 per day in the US
The US Centers for Medicare and Medicaid Services has assigned a maximum payment of $7,919.86 per
patient administered cefiderocol, which includes the New Technology Add-On Payment (86).
An analysis of cost effectiveness was performed comparing cefiderocol to colistin-based regimens for
the treatment of cUTI and HABP/VABP caused by confirmed CR pathogens (87). This analysis found
cefiderocol to be a cost-effective option for cUTI and HABP/VABP against the comparators. A decision-
tree model was created to determine the cost-effectiveness of cefiderocol versus colistin-based
regimens for the treatment of CR cUTI and CR nosocomial pneumonia infections in the US. A
deterministic sensitivity analysis (DSA) was conducted that varied both benefits and costs, and a
probabilistic sensitivity analysis (PSA) was based on 5000 simulations. These analyses showed that
cefiderocol was cost-effective versus colistin-based regimens with an ICER: $14,616/QALY; $8,683
incremental costs and 0.59 incremental QALY (87).
12. Summary of regulatory status and market availability of the medicine

Cefiderocol has been approved for use in both the US and Europe, and regulatory details are included in
Table 18.
Table 18. Regulatory status of the technology
Organization
Verbatim wording of the (expected) Date of
issuing Launch Status
indication(s) approval
approval
FETROJA® is indicated in patients 18 Launched in the US

years of age or older for the treatment of November 14,
FDA on February 24,
complicated urinary tract infections 2019
2020
(cUTIs), including pyelonephritis caused
32
by the following susceptible Gram-

negative microorganisms: Escherichia
coli, Klebsiella pneumoniae, Proteus
mirabilis, Pseudomonas aeruginosa,
and Enterobacter cloacae complex
FETROJA is indicated in patients 18

years of age or older for the treatment of
hospital-acquired bacterial pneumonia
and ventilator-associated bacterial
pneumonia, caused by the following
September 27,
susceptible Gram-negative
2020
microorganisms: Acinetobacter
baumannii complex, Escherichia coli,
Enterobacter cloacae complex,
Klebsiella pneumoniae, Pseudomonas
aeruginosa, and Serratia marcescens
Launched in the UK
on September 15,
Fetcroja is indicated for the treatment of
infections due to aerobic Gram-negative 2020; launched in
EMA April 23, 2020
organisms in adults with limited Germany on
treatment options November 23,
2020*
* Reimbursement and HTA assessments are in process in other EU markets; launch will occur when
reimbursement is secured. Early access programs are in place for patients who may need access in the
interim.
13. Availability of pharmacopoeia standards (British Pharmacopoeia,

International Pharmacopoeia, United States Pharmacopoeia, European
Pharmacopoeia)
Cefiderocol is not currently available in any pharmacopoeia standards.
33
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Appendix A
To identify all relevant studies for cefiderocol and comparators, a comprehensive systematic literature
review was conducted comprising in vitro and in-vivo studies, as well as any comparative or non-
comparative studies and RCTs (including cross-over RCTs). The literature search was conducted in the
databases and information resources shown in Table 1. The same databases and information sources
were searched for the most recent search update in September 2020.
Table 1. Databases and information sources searched

Database / information source Interface / URL Coverage
MEDLINE ALL Ovid SP Biomedical journal literature
PubMed https://www.ncbi.nlm.nih.gov/pubmed/ Biomedical journal literature
Embase OvidSP Biomedical journal literature
Cochrane Central Register of Randomized and quasi-
Wiley Cochrane Library
Controlled Trials (CENTRAL) randomized controlled trials
Cochrane Database of
Wiley Cochrane Library Systematic reviews
Systematic Reviews
Database of Abstracts of
CRD website Systematic reviews
Reviews of Effects (DARE)
Health Technology Assessment
CRD website Health technology assessment
(HTA)
Science, social science, arts,
Web of Science http://apps.webofknowledge.com/
humanities
Life sciences and biomedical
BIOSIS Citation Index http://apps.webofknowledge.com/
research
Records for registered clinical
ClinicalTrials.gov https://www.clinicaltrials.gov/ct
studies
WHO International Clinical Trials
http://www.who.int/ictrp/en/ Trial registration data sets
Registry Platform (WHO ICTRP)
Recent research published as conference abstracts were identified by searching Embase (which indexes
a significant number of conference publications). In addition, where the following conferences
(identified as highly relevant by the research team) were not indexed in Embase from 2016 to 2019, we
conducted hand-searches for abstracts via conference webpages:
x European Congress of Clinical Microbiology & Infectious Diseases (ECCMID)

x IDWeek
x European Respiratory Society (ERS) International Congress
We also checked the reference lists of any relevant reviews or systematic reviews for eligible records.
Three hundred sixteen (316) records were assessed for relevance. 49 records were excluded after an
39
assessment of the information in the title and abstract. 267 full text documents were assessed, and 153
records were included (Table 2). The initial review included publications through April 2020 and
additional records were added through September 2020. Records were excluded if they were a review,
an opinion piece, or systematic review for reference checking; had an ineligible study design,
intervention, or outcomes; or were unobtainable.
Table 2. Studies identified in a systematic literature review through September 2020. Studies are
characterized into the following categories: In vitro, In vitro assessment of specific clinical samples, In
vivo, Clinical, Mixed categories, Modeling, Systematic review protocol.
Reference
In vitro
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gram-negative pathogens including multi-drug resistant bacteria: structure activity relationship. Eur J
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Aoki T, Yoshizawa H, Yamawaki K, Yokoo K, Sato J, Hisakawa S, et al. Cefiderocol (S-649266): A new
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gram negative-pathogens including multi-drug resistant bacteria: structure activity relationship. Abstr.
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Boyd S, Anderson K, Albrecth V, Campbell D, Karlsson MS, JK R. In vitro activity of cefiderocol against
multi-drug resistant carbapenemase-producing gramnegative pathogens. In: IDWeek, 2017.
Coppi M, Antonelli A, Baglio G, Giani T, GM R. Activity of cefiderocol on a reference collection of
carbapenemase-,ESBL-, and acquired class C beta-lactamases-producing gram-negative pathogens. In:
ECCMID, 2019.
Delgado-Valverde M, Conejo MC, Serrano-Rocha L, Fernandez-Cuenca F, AP H. Activity of cefiderocol
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Acinetobacter baumannii, Pseudomonas aeruginosa and Stenotrophomonas maltophilia. In: ECCMID,
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Dobias J, Denervaud V, Poirel L, P N. Activity of the novel siderophore cephalosporin cefiderocol (S-
649266) against Gramnegative pathogens. In: ECCMID, 2017.
Dobias J, Denervaud-Tendon V, Poirel L, Nordmann P. Activity of the novel siderophore cephalosporin
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Hackel MA, Tsuji M, Yamano Y, Echols R, Karlowsky JA, Sahm DF. Reproducibility of broth
microdilution MICs for the novel siderophore cephalosporin, cefiderocol, determined using iron-
depleted cation-adjusted Mueller-Hinton broth. Diagn Microbiol Infect Dis. 2019;94(4):321-25.
Huband MD, Ito A, Tsuji M, Sader HS, Fedler KA, Flamm RK. Cefiderocol mic quality control ranges in
iron-depleted cation-adjusted mueller-hinton broth using a clsi m23-a4 multi-laboratory study design.
Diagn Microbiol Infect Dis. 2017;88(2):198-200.
Ishii Y, Horiyama T, Nakamura R, Fukuhara N, Tsuji M, Yamano Y, et al. S-649266, a novel siderophore
cephalosporin: III. Stability against clinically relevant beta-lactamases. In: ICAAC, 2014. 1557.
Ito A, Ishibashi N, Ishii R, Tsuji M, Maki H, Sato T, et al. Changes of responsible iron-transporters for
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Ito A, Kohira N, Bouchillon SK, West J, Rittenhouse S, Sader HS, et al. In vitro antimicrobial activity of
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Ito A, Nishikawa T, Ishii R, Kuroiwa M, Ishioka Y, Kurihara N, et al. Mechanism of Cefiderocol high MIC
mutants obtained in non-clinical FoR studies In: IDWeek, 2018.
Ito A, Nishikawa T, Matsumoto S, Fukuhara N, Nakamura R, Tsuji M, et al. S-649266, a novel
siderophore cephalosporin: II. Impact of active transport via iron regulated outer membrane proteins
on resistance selection. Abstract F-1563. In: ICAAC, 2014.
Ito A, Nishikawa T, Matsumoto S, Yoshizawa H, Sato T, Nakamura R, et al. Siderophore cephalosporin
cefiderocol utilizes ferric iron transporter systems for antibacterial activity against pseudomonas
aeruginosa. Antimicrob Agents Chemother. 2016;60(12):7396-401.
Ito A, Nishikawa T, Ota M, Ito-Horiyama T, Ishibashi N, Sato T, et al. Stability and low induction
propensity of cefiderocol against chromosomal AmpC beta-lactamases of pseudomonas aeruginosa
and enterobacter cloacae. J Antimicrob Chemother. 2018;73(11):3049-52.
Ito A, Nishikawa T, Ota M, Ito-Horiyama T, Ishibashi N, Sato T, et al. Stability and low induction
propensity of cefiderocol against chromosomal AmpC beta-lactamases of pseudomonas aeruginosa
and enterobacter cloacae. J Antimicrob Chemother. 2019;74(2):539.
Ito A, Sato T, Ota M, Takemura M, Nishikawa T, Toba S, et al. In vitro antibacterial properties of
cefiderocol, a novel siderophore cephalosporin, against gram-negative bacteria. Antimicrob Agents
Chemother. 2018;62(1):1-11.
Ito-Horiyama T, Ishii Y, Ito A, Sato T, Nakamura R, Fukuhara N, et al. Stability of novel siderophore
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Jacobs M, Bbajaksouzian S, Good C, Hujer K, Hujer A, R B. In vitro activity of cefiderocol (S-649266), a
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Jacobs MR, Abdelhamed AM, Good CE, Rhoads DD, Hujer KM, Hujer AM, et al. ARGONAUT-I: activity
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Jacobs MR, Abdelhamed AM, Good CE, Rhoads DD, Hujer KM, Hujer AM, et al. In vitro activity of
cefiderocol (S-649266), a siderophore cephalosporin, against enterobacteriaceae with defined
extended-spectrum β-lactamases and carbapenemases. In: IDWeek, 2018.
Kanazawa S, Sato T, Kohira N, Ito-Horiyama T, Tsuji M, Yamano Y. Susceptibility of imipenem-
susceptible but meropenem-resistant blaIMP-6-carrying enterobacteriaceae to various antibacterials,
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Kohira N, Nakamura R, Ito A, Nishikawa T, Ota M, Sato T, et al. Resistance acquisition studies of
cefderocol by serial passage and in vitro pharmacodynamic model under human simulated exposure.
In: ASM Microbe, Atlanta; 2018.
Kohira N, Oota M, Nishikawa T, Kuroiwa M, Ishioka Y, Naoko K, et al. Frequency of resistance
acquisition and resistance mechanisms to cefiderocol. In: ASM Microbe, Atlanta; 2018.
Kohira N, West J, Ito A, Ito-Horiyama T, Nakamura R, Sato T, et al. In vitro antimicrobial activity of a
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Poirel L, Kieffer N, Nordmann P. Stability of cefiderocol against clinically significant broad-spectrum
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Application for inclusion of FETCROJA/FETROJA on WHO EML

Application for inclusion of

Applicant: Point of Contact:

Date of Submission: November 30, 2020

Figure 5. Aggregated resistance rates of Enterobacter aerogenes/cloacae to fluoroquinolones,

1. Summary statement of the proposal for inclusion, change or

Cefiderocol is a parenteral siderophore cephalosporin antibiotic discovered and developed by Shionogi.

2. Relevant WHO technical department and focal point (if applicable)

3. Name of organization consulted and /or supporting the application

4. International Nonproprietary Name (INN) and Anatomical

5. Dose form(s) and strength(s) proposed for inclusion; including

Cefiderocol is currently being investigated in pediatric populations in the US (NCT04215991/EudraCT

6. Whether listing is requested as an individual medicine or as

7. Treatment details (requirements for diagnosis, treatment and

Figure 1: Cefiderocol mechanism of action (from Morgan et. al. (4))

Table 1. Administration and dosing of cefiderocol

Reference WHO guidelines and/or other evidence-based clinical guidelines

x Pyelonephritis and cUTIs caused by CRE or DTR-P. aeruginosa

Consideration of any additional requirements associated with treatment, such as

8. Information supporting the public health relevance.

Figure 2. Worldwide carbapenem resistance

Source: CDC 2013(24); ECDC 2017(21); Mendes et al.(30); Kiratisin et al.(31)

Table 2. Prevalence of CR Gram-negative infections in the EU-5

Figure 3. Aggregated resistance rates of A. baumanniito carbapenems, fluoroquinolones or ceftazidime

Figure 4. Aggregated resistance rates of P. aeruginosato ceftazidime, fluoroquinolones or carbapenems

Figure 5. Aggregated resistance rates of Enterobacter aerogenes/cloac

Figure 6. Aggregated resistance rates of K. pneumoniae to carbapenems, fluoroquinolones,

Assessment of current use

Likely impact of treatment on the disease

9. Review of benefits: summary of evidence of comparative

P. aeruginosa, and MDR Enterobactericeae. Cefiderocol was also found to be non-inferior to

Table 4. GRADE quality assessment for the cefiderocol clinical trials

Summary of available data and estimates of comparative effectiveness

1a) SIDERO-WT results for all Gram-negative isolates (50-52)

Table 5: Percent of isolates with in vitro susceptibility to cefiderocol, colistin, ceftolozane-tazobactam

Polymyxin E Ceftolozane/ Ceftazidime/

All Gram-negative 95.49b

1b) SIDERO-WT-based analysis of difficult-to-treat resistant (DTR) pathogens (57)

A subsequent analysis focused on a DTR subset of pathogens, which were non-susceptible to

Table 6. Breakpoints for non-ƐƵƐĐĞƉƚŝďŝůŝƚǇƵƐĞĚŝŶĚĞĨŝŶŝƚŝŽŶŽĨ

Table 7. Percent of isolates with in vitro susceptibility to cefiderocol, ceftazidime/avibactam,

In addition, 98.7% of carbapenem-non-susceptible (CarbNS) Enterobacteriaceae, and 96.4% of CarbNS

Table 8. Percent of isolates with in vitro susceptibility to cefiderocol, ceftazidime/avibactam,

2) SIDERO-CR-2014-2016 study (protocol S-649266-EF-115-N)

Table 9. Percent of isolates with in vitro susceptibility to cefiderocol, ceftazidime/avibactam,

Clinical study results (clinical outcomes)

APEKS-cUTI was a Phase 2, multi-center (multinational), double-blind, randomized, active-controlled,

the sensitivity analysis (composite clinical and microbiological response in microbiologically-evaluable

Figure 8. Primary efficacy results: Composite outcome at TOC by predefined subgroups

Table 10. Summary of Microbiological and Clinical Outcomes

No new infections were noted

Compassionate Use and Expanded Access Programs

10. Review of harms and toxicity: summary of evidence of safety

Table 15. Summary of on-going or planned human studies

78 to 85 planned subjects, 4:1

Description of the adverse effects/reactions and estimates of their frequency

Vascular disorders 0 0 1 (1.0) 0 0 0 1 (0.2) 0

- Hypertension 0 0 1 (1.0) 0 0 0 1 (0.2) 0

Summary of available data (appraisal of quality, summary of results) and summary of

11. Summary of available data on comparative cost and cost-