All rights reserved 1 Core Submission Dossier PTJA11 Cefiderocol For the treatment of infections due to aerobic Gram-negative organisms in adults with limited treatment options Submitted by: Shionogi Disclaimer: The sole responsibility for the content of this document lies with the submitting manufacturer and neither the European Commission nor EUnetHTA are responsible for any use that may be made of the information contained therein. Contact details for administrative purposes Shionogi BV 33 Kingsway London WC2B 6UF Email address: [email protected]For agency completion Date of receipt: 14-04-2020 Version 3: Amended dossier reflecting additional PK/PD analysis. Identifier: PTJA11
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Core Submission Dossier PTJA11
Cefiderocol For the treatment of infections due to aerobic Gram-negative organisms in adults with limited
treatment options
Submitted by: Shionogi
Disclaimer: The sole responsibility for the content of this document lies with the submitting manufacturer and neither the European Commission nor EUnetHTA are responsible for any use that may be made of the information contained therein.
Contact details for administrative purposes Shionogi BV 33 Kingsway London WC2B 6UF Email address: [email protected]
For agency completion Date of receipt: 14-04-2020 Version 3: Amended dossier reflecting additional PK/PD analysis. Identifier: PTJA11
All rights reserved 2
Abbreviations
A Aerobic
AAT Appropriate antibacterial therapy
ABC transporter ATP-binding cassette transporter
ABSSSI Acute bacterial skin and skin structure infection
Ac-BSI Acinetobacter spp. Bacteraemia
AE Adverse event
AET Appropriate empirical therapy
ALAT Asociación Latinoamericana del Tórax
AMK Amikacin
AMR Antimicrobial resistance
AN Anaerobic
AR Antimicrobial-resistance
AS Antimicrobial susceptibility
AST Antimicrobial susceptibility tests
AT Antibacterial therapy
ATS American Thoracic Society
AUC Area under the curve
BAT Best available therapy
BD Becton Dickinson
BIA Budget impact analysis
BIM Budget impact model
BAL Bacterial β-lactamase
BLI β-lactamase inhibitor
BSI Bloodstream infection
BSIMRS Bloodstream infection mortality risk score
CAI Community-acquired infection
CarbNS Carbapenem non-susceptible
CASR Carbapenem- and ampicillin-sulbactam-resistant
CAZ Ceftazidime/avibactam
CDC Centres for Disease Control and Prevention
CDI Clostridium difficile infection
CFU Colony forming unit
CHMP Committee for Medicinal Products for Human Use
NICE National Institute of Health and Care Excellence
NR Non-resistant
NS Non- survivors
OM Osteomyelitis
OMT Outer membrane transporters
OR Odds ratio
OXA Oxacillinase
PBC Positive blood culture
PBPs Penicillin-binding proteins
PCR Polymerase Chain Reaction
PD Pharmacodynamic
PDCO Paediatric Committee
PDR Pan-drug-resistant
PEG Percutaneous endoscopic gastroscopy
PER Pseudomonas extended resistant β-lactamases
PK Pharmacokinetic
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PP Per Protocol
PTA Probability of target attainment
q8h Every 8 hours
R Resistant
RCT Randomized controlled trial
RESP Respiratory tract
RR Relative risk
r-GNR Resistant gram-negative rod
RTI Respiratory tract infection
S Survivors
SAE Serious adverse event
SC Subcutaneous
SCCM Society of Critical Care Medicine
SD Standard deviation
SEFH Spanish Society of Hospital Pharmacies
SEMPSPH Spanish Society of Preventive Medicine, Public Health and
Hygiene
SICU Surgical intensive care unit
SIS Surgical Infection Society
SMC Siderophore monobactam conjugate
sNDA Supplemental new drug application
SOC Standard of care
spp Species
SSI Surgical site infection
TOC Test of Cure
tRNA Transfer ribonucleic acid
UTI Urinary tract infection
VAP Ventilator-acquired pneumonia
VABP Ventilator-associated bacterial pneumonia
VIM Verona integrin-encoded metallo-β-lactamase
w/wo With or without
WHO World Health Organization
WSES World Society of Emergency Surgery
XDR Extensively drug-resistance
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Contents
EXECUTIVE SUMMARY .......................................................................................... 14 1 Description and technical characteristics of the technology .......................... 23 1.1 Characteristics of the technology ................................................................... 25
1.1.1 Cefiderocol Structure .......................................................................... 26 1.1.2 Mechanism of action and cell entry .................................................... 27
1.1.3 Stability against β-lactamases ............................................................ 28 1.2 Regulatory status of the technology .............................................................. 29 2 Health problem and current clinical practice .................................................. 31 2.1 Overview of the disease or health condition .................................................. 32
2.1.1 Overview of Gram-negative bacteria .................................................. 33 2.1.2 Antimicrobial resistance ...................................................................... 35 2.1.3 Overview of infection sites .................................................................. 39
2.1.4 Risk and prognostic factors for MDR and CR infections ..................... 41 2.1.5 Epidemiology ...................................................................................... 42 2.1.6 Mortality .............................................................................................. 47 2.1.7 Quality of Life ...................................................................................... 48
2.1.8 Disability Adjusted Life Years (DALYs) ............................................... 48 2.1.9 Delayed effective therapy ................................................................... 49
2.2 Target population ........................................................................................... 52
2.3 Clinical management of the disease or health condition ................................ 57 2.3.1 Key information on currently available treatments in Europe .............. 59
2.3.2 Site-specific vs. pathogen-specific guidelines..................................... 63 2.3.3 Specific recommendations.................................................................. 63
2.3.4 Specific considerations of CR infections ............................................. 63 2.4 Comparators in the assessment .................................................................... 87
2.4.1 General considerations ....................................................................... 87 2.4.2 Selection of relevant comparators for the assessment ....................... 89
3 Current use of the technology........................................................................ 94
3.1 Current use of the technology........................................................................ 95 3.2 Reimbursement and assessment status of the technology ........................... 96
4 Investments and tools required...................................................................... 97 4.1 Requirements to use the technology ............................................................. 98
4.1.1 Conditions for use ............................................................................... 99
4.1.2 Good stewardship and societal considerations................................... 99 5 Clinical effectiveness and safety .................................................................. 102 5.1 Identification and selection of relevant studies ............................................ 105
5.1.2 Study categorisation ......................................................................... 111 5.2 Relevant studies .......................................................................................... 112 5.3 Main characteristics of studies..................................................................... 134
5.3.1 APEKS-cUTI STUDY ........................................................................ 144 5.3.2 APEKS-NP STUDY .......................................................................... 151
5.3.3 CREDIBLE-CR STUDY .................................................................... 155 5.3.4 Summary of compassionate use cases and published evidence ...... 160
5.4 Individual study results (clinical outcomes) .................................................. 164 5.4.1 Individual study results (in vitro surveillance outcomes) ................... 164
5.4.2 Individual study results (PK/PD data, study report S-649266-CPK-004-B) ...................................................................................................... 189
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5.4.3 Retrospective analysis of cefiderocol and comparators by population PK/PD simulation .............................................................................. 192
5.4.4 Clinical study results (clinical outcomes) .......................................... 194 5.4.5 Resistance against Cefiderocol ........................................................ 233
5.5 Individual study results (safety outcomes) ................................................... 259 5.5.1 Overall safety results: pooled analysis and individual studies: APEKS-
cUTI, APEKS-NP, and CREDIBLE CR ............................................. 259 5.5.2 Safety analyses by clinical trial ......................................................... 265
5.6 Conclusions ................................................................................................. 287 5.6.1 Evidence to support use of cefiderocol in patients with infections by
suspected MDR/CR pathogens: ....................................................... 289 5.6.2 Evidence to support use of cefiderocol in patients with infections by
confirmed CR pathogens: ................................................................. 291 5.6.3 Quality of Life .................................................................................... 293 5.6.4 Comparators ..................................................................................... 293
5.7 Strengths and limitations ............................................................................. 297 5.7.1 Risk of bias assessment ................................................................... 297
List of Figures Figure 1: Cefiderocol structure ............................................................................................ 27 Figure 2: Cefiderocol mechanism of cell entry ..................................................................... 28 Figure 3: Antibacterial activity against β-lactamase-producing pathogens ........................... 28 Figure 4: Classification of Gram-negative bacteria .............................................................. 34 Figure 5: Global burden of AMR .......................................................................................... 35 Figure 6: Mechanisms of beta lactam bacterial resistance .................................................. 37 Figure 7: Hospital-acquired infections in acute care hospitals (EU/EEA 2011-2012) ........... 40 Figure 8: Worldwide carbapenem resistance ...................................................................... 42 Figure 9: Prevalence of CR Gram-negative infections in the EU-5 ...................................... 43 Figure 10: Epidemiology of carbapenemases in EU 5 ......................................................... 44 Figure 11: Confirmed carbapenemase-producing Enterobacteriaceae isolates (Public Health England: 2008–17) .............................................................................................................. 45 Figure 12: Distribution of carbapenem resistance mechanisms in Enterobacteriaceae species in the Europe.......................................................................................................... 45 Figure 13: Summary of effect of appropriate versus inappropriate initial antibacterial therapy on mortality ......................................................................................................................... 51 Figure 14: Summary of effect of delay versus no delay in receiving initially appropriate antibacterials on mortality ................................................................................................... 51 Figure 15: Summary of effect of appropriate versus inappropriate therapy on treatment failure .................................................................................................................................. 52 Figure 16 - Treatment of patients with highly suspected infection by CR or other MDR GN pathogens ........................................................................................................................... 55 Figure 17: Treatment of patients with confirmed infection by carbapenem-resistant or other MDR Gram-negative pathogen ........................................................................................... 55 Figure 18: Current treatment approach for bacterial infections ............................................ 57 Figure 19: Current clinical reasoning for the treatment of serious MDR Gram-negative infections ............................................................................................................................. 59 Figure 20 - Search strategy for OVD MEDLINE ALL ......................................................... 106 Figure 21 - PRISMA flow diagram of record selection process .......................................... 111 Figure 22: APEKS-cUTI study design ............................................................................... 144 Figure 23: Subject disposition (all randomized subjects) ................................................... 145 Figure 24: Distribution of uropathogens (mITT population) ................................................ 150 Figure 25: APEKS-NP study design and patient flow ........................................................ 152 Figure 26: Patient demographics and baseline characteristics .......................................... 153 Figure 27: CREDIBLE-CR study design and patient flow .................................................. 156 Figure 28: Subjects disposition (all randomized subjects) ................................................. 157 Figure 29: APEKS-cUTI study design and endpoints ........................................................ 196 Figure 30: Primary efficacy results: Composite outcome at TOC in the MITT population .. 197 Figure 31: Primary efficacy results: Composite outcome at TOC by predefined subgroups198 Figure 32: Maximum Network Chart for Network Meta-analysis ........................................ 209 Figure 33: Network Diagram for Microbiological Eradication Secondary Outcome ............ 209 Figure 34: Microbiological Eradication Rates at TOC - Frequentist Analysis ..................... 210 Figure 35: Microbiological Eradication Rates at TOC - Bayesian Analysis ........................ 210 Figure 36: Network Diagram for Clinical Cure Outcome .................................................... 210 Figure 37: Clinical cure rates at TOC - Frequentist Analysis ............................................. 211 Figure 38: Clinical Cure rate at TOC - Bayesian Analysis ................................................. 211 Figure 39: Clinical cure rates at FU - Frequentist Analysis ................................................ 211 Figure 40: APEKS-NP study design .................................................................................. 213 Figure 41: All-cause Mortality (mITT) ................................................................................ 214 Figure 42: Primary efficacy results: Day 14 All-cause Mortality by Subgroups .................. 215 Figure 43: Day 14 and Day 28 all-cause mortality according to MIC for meropenem ........ 218 Figure 44: Microbiological eradication by MIC at EOT ....................................................... 219 Figure 45: CREDIBLE CR study design ............................................................................ 223
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Figure 46: Clinical cure by Clinical Diagnosis and time point ............................................. 224 Figure 47: Microbiological eradication by Clinical Diagnosis and time point ...................... 224 Figure 48: Clinical and Microbiological Outcomes at TOC in Enterobacteriaceae by Carbapenemase or Porin Channel Mutation (CR Micro-ITT Population) ........................... 226 Figure 49: Clinical and Microbiological Outcomes in Metallo Β-lactamase Producing Gram-negative Pathogens (CR Micro-ITT Population) ................................................................ 226 Figure 50: All-cause Mortality Rates by Type of Infection .................................................. 227 Figure 51: Mortality rates comparison across studies ........................................................ 230 Figure 52: Network Diagram for Safety Analysis ............................................................... 271 Figure 53: Safety Analysis for All Adverse Events - Frequentist Analysis .......................... 271 Figure 54: Network for safety analysis for Treatment related AEs ..................................... 271 Figure 55: safety analysis for Treatment related AEs – Frequentist analysis ..................... 271
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List of Tables Table 1: Features of the technology .................................................................................... 25
Table 2: Administration and dosing of the technology ......................................................... 25
Table 3: Regulatory status of the technology ...................................................................... 29
Table 4: List of the highest priority bacteria (WHO) ............................................................. 35
Table 5: In vitro activity profile of antibacterials for GN Infections with limited treatment options ................................................................................................................................ 39
Table 6: Most common CR causal pathogens across available EU-5 data sources ............ 43
Table 7: Proportion of CR infection sites in the EU-5........................................................... 44
Table 8: Overview of disease burden according to the infection site ................................... 46
Table 9: In Vitro Gram-negative activity profiles .................................................................. 54
Table 10a: Relevant guidelines for diagnosis and management – MDR/GN Bacteria ......... 65
Table 11b: Relevant guidelines for diagnosis and management – HAP/VAP(HCAP) .......... 70
Table 11c: Relevant guidelines for diagnosis and management – cUTI .............................. 75
Table 11d: Relevant guidelines for diagnosis and management – BSI/Sepsis .................... 78
Table 11e: Relevant guidelines for diagnosis and management- cIAI ................................. 83
Table 22: Summary of study regimen for Gram-negative pathogen at day 1 and day 2 (CR-mITT population) ............................................................................................................... 159
Table 23: Baseline Gram-negative pathogens, n (%) ........................................................ 160
Table 24: Patient demographics and baseline characteristics ........................................... 162
Table 26: In vitro activity data for all tested clinical strains (SIDERO-WT-2014/2015/2016 and Proteeae) of cefiderocol (at MIC of 4mg/L) versus ceftazidime-avibactam, ceftolozane-tazobactam, and colistin .................................................................................................... 167
Table 27: In vitro activity of cefiderocol and comparators against Gram-negative bacilli isolated by 55 clinical laboratories in Europe in 2015 (n=5352) ......................................... 170
Table 28: In vitro activity of cefiderocol and comparators against non-fermenters ............. 172
Table 29: Breakpoints for non-susceptibility used in definition of DTR (μg/mL) ................. 173
Table 30: Susceptibility of cefiderocol and comparators to pathogens .............................. 173
Table 31: In vitro activity data for CR Gram-negative pathogens (SIDERO-WT-2016-2017) of cefiderocol versus ceftazidime-avibactam, ceftolozane-tazobactam and colistin ............... 174
Table 32: Number of MEM-NS isolates by year and species ............................................. 175
Table 33: Number of MEM-NS isolates by country and species ........................................ 175
Table 34: Susceptibility breakpoints according to the CLSI (cefiderocol) and/or EUCAST (all comparators) ..................................................................................................................... 176
Table 35: Percentage of susceptibility of MEM-NS A. baumannii complex by country ....... 177
Table 36: Percentage of susceptibility of MEM-NS P. aeruginosa complex by country ...... 177
Table 37: Percentage of susceptibility of MEM-NS K. pneumoniae by country .................. 177
Table 38: Percentage of susceptibility of other MEM-NS Enterobacteriaceae by country .. 177
Table 39: In vitro activity data for all tested clinical strains (SIDERO-CR 2014-2016) of cefiderocol versus ceftazidime-avibactam, ceftolozane-tazobactam, and colistin .............. 178
Table 40: MIC of cefiderocol and comparators in Germany ............................................... 179
Table 41: MIC of cefiderocol and comparators in Greece .................................................. 180
Table 42: MIC of cefiderocol and comparators in Spain .................................................... 181
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Table 43: MIC of cefiderocol and comparators against in United Kingdom and Ireland ..... 182
Table 44: Activity of antimicrobial agents tested against carbapenem-resistant P. aeruginosa and S. maltophilia ............................................................................................................. 183
Table 45: MIC of cefiderocol and comparators for MDR-GN isolated ................................ 184
Table 46: Number of cefiderocol non-susceptible isolated in global surveillance studies (MIC ≥8 μg/mL).......................................................................................................................... 185
Table 47: EUCAST breakpoints for cefiderocol ................................................................. 186
Table 48: Susceptibility to Cefiderocol and comparators in all sites of infections for MDR3 pathogens ......................................................................................................................... 187
Table 49- Theoretical success of antibacterial therapy in Gram‐negative 3MDR pathogens in gastrointestinal site of infections (A) Pneumonia; (B) cUTI; (C) BSI; (D) Gastrointestinal .. 187
Table 50: Summary table Theoretical percentage of success for Gram‐negative antibacterial
therapy on aerobic Gram‐negative pathogens in different infection type ........................... 188
Table 51: PTA per infectious disease renal function, and dose ......................................... 190
Table 52. Estimated CFR for MIC distributions corresponding to Enterobacterales and Pseudomonas spp. More simulation results for corresponding PTA, MIC and T>MIC target values are shown in Appendix C. The applied MIC distributions can be seen in Appendix D of the study report. ............................................................................................................ 193
Table 53: Endpoint Analysis as per EUnetHTA Request ................................................... 194
Table 54: Summary for Composite of Clinical and Microbiological Outcome by Time Point (Microbiological Intent-to-Treat Population) ....................................................................... 197
Table 55: Composite of Clinical Response and Microbiological Outcome per Pathogen at TOC (microbiological ITT population) ................................................................................ 199
Table 56: Summary of Clinical Outcomes per Subject by Time Point (Microbiological Intent-to-Treat Population) .......................................................................................................... 200
Table 57: Summary of Clinical Outcome per Uropathogen (E. coli, K. pneumoniae, P. aeruginosa, and P. mirabilis) by Time Point (Microbiological ITT Population) .................... 201
Table 58: Summary of Microbiological Outcome per Subject by Time Point (Microbiological ITT Population) ................................................................................................................. 203
Table 59: Summary of Microbiological Outcome per Uropathogen (E. coli, K. pneumoniae, P. aeruginosa, P. mirabilis) by Time Point (Microbiological ITT Population)........................... 205
Table 60: Day 14 All-cause Mortality (mITT and ME-PP Populations) ............................... 214
Table 63: Clinical and microbiological outcome per baseline pathogen ............................. 217
Table 64: Microbiological and Clinical Outcome for the Meropenem-non-susceptible Subgroup (mITT Population) ............................................................................................. 219
Table 65: Susceptibility and effectiveness model predicting outcomes for Cefiderocol versus comparators in UTI ........................................................................................................... 221
Table 66: Susceptibility and effectiveness model predicting outcomes for Cefiderocol versus comparators in Pneumonia ............................................................................................... 221
Table 67: Clinical cure and microbiological eradication by baseline CR-pathogen ............ 225
Table 68: Summary for All-cause Mortality in the Study (Intent to treat Population) .......... 227
Table 69: Summary for all-cause mortality overall by pathogens subgroup (Enterobactereacea and non-fermenters) .......................................................................... 229
Table 70: CREDIBLE-CR study: Mortality subgroup Analysis for Subjects with A. baumannii (safety population) ............................................................................................................ 229
Table 71: Mortality and serious adverse events ................................................................ 231
Table 72: Summary of MIC shift ........................................................................................ 234
Table 73a: Methods of data collection and analysis of Mortality ........................................ 235
Table 80b: Methods of data collection and analysis of Clinical outcomes .......................... 237
Table 80c: Methods of data collection and analysis of Composite microbiological eradication and cure ............................................................................................................................ 245
Table 80d: Methods of data collection and analysis of Microbiological outcomes .............. 249
Table 80e: Methods of data collection and analysis of Susceptibility rates ........................ 258
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Table 81: Dose and Duration of Exposure to cefiderocol* (Number of Patients by Indication) ......................................................................................................................................... 259
Table 82: Subjects with Treatment Related Adverse Events by System Organ Class and Preferred Term (All Phase II/III Studies) Safety Population ............................................... 261
Table 83: Summary of duration of exposure (safety population) ........................................ 266
Table 85: Number (%) of subjects with adverse events by maximum severity (safety population) ........................................................................................................................ 268
Table 86: Number (percent) of subjects with serious adverse events (SAEs) by organ class and preferred term (safety population) .............................................................................. 269
Table 87: Number (%) of subjects with treatment-related serious adverse events (SAEs) 270
Table 89 – Number (percent) of subjects with serious adverse events (SAEs) by organ class and preferred term (safety population) .............................................................................. 275
Table 91: Subjects with Treatment-related Adverse Events by Preferred Term (Safety Population) ........................................................................................................................ 280
Table 92: Subjects with Serious Adverse Events by System Organ Class and Preferred Term (Safety Population) .................................................................................................. 281
Table 93: Limitations to detect adverse events in clinical trial programmes ....................... 283
Table 94: Methods of data collection and analysis of AE, TEAE and SAE ......................... 284
significant safety and tolerability concerns [e.g. colistin, tigecycline]) [31-34].
Even recently approved combinations of cephalosporins with established β-lactam/β-
lactamase inhibitors have activity against MDR Gram-negative infections, including P.
aeruginosa, but their limitations include a lack of activity against metallo-β-lactamase-
producing organisms and these new antibacterials remain vulnerable to resistance
mechanisms due to porin channel mutations or overexpression of efflux pumps [28, 35-43].
Despite having high rates of renal toxicity, the broad Gram-negative spectrum of colistin and
polymyxin B mean that they are still used in the absence of alternative effective treatment
options for increasingly emerging CR in Gram-negative bacteria [31].
New treatments that can overcome the known resistance mechanisms, are therefore needed,
contributing to more effective eradication of MDR pathogens and increase antibacterial
diversity, thus, supporting good stewardship and the overall effectiveness of the existing
arsenal of antibacterials.
CEFIDEROCOL overcomes the 3 main mechanisms of antibacterial resistance present
in Gram-negative pathogens and is active on WHO critical priority pathogens
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Cefiderocol is the first siderophore cephalosporin [44] to be approved. The cephalosporin core
of cefiderocol exerts it’s activity through inhibition of Gram-negative bacterial cell wall
biosynthesis leading to cell lysis. Its unique molecular structure catecholate siderophore
moiety, exploits the bacteria’s own active iron uptake mechanism via siderophores to enter
the periplasmic space of GNB where it exerts its bactericidal activity. This is a novel
mechanism of bacterial cell entry which means that cefiderocol, unlike other antibacterials,
bypasses pathways traditionally used by other antibacterials such as efflux pumps or porin
channels, which bacteria can regulate to reduce their exposure to antibacterials. Cefiderocol
also has a higher stability to both serine- and metallo-type β -lactamases, key enzymes
rendering resistance to β–lactam antibacterials, including carbapenems. All these factors
contribute to cefiderocol’s unique breadth of activity and efficacy, covering a wide range of
aerobic, GN bacteria, demonstrated by its potent activity (both in vitro and in-vivo) against all
three WHO priority CR pathogens (Enterobacteriaceae, A. baumannii and P. aeruginosa) [29,
30, 45-49]. In addition, cefiderocol has in vitro activity against intrinsically CR Stenotrophomas
maltophilia and Burkholderia cepacia [30].
The dosing regimen of cefiderocol is 2g administered every 8 hours by IV infusion over 3 hour
period, with treatment duration dependent on the site of infection, e.g. 5-10 days for cUTI and
cIAI and 7-14 days for hospital-acquired pneumonia, but treatment up to 21 days may be
required [50].
The indication for cefiderocol is expected to be:
Fetcroja is indicated for the treatment of infections due to aerobic Gram-negative
organisms in adults with limited treatment options.
This indication will therefore be pathogen focused, not restricted to any specific site of infection and supports the use of cefiderocol in two types of patients:
Hospitalised patients with suspected (but prior laboratory confirmation) MDR/CR
infection who are critically ill and require immediate antibacterial treatment that
provides full cover against CR pathogens and potential resistant mechanisms, to
avoid the risk of rapid clinical deterioration (with the option to de-escalate to a more
targeted treatment when the pathogen and susceptibility profile is subsequently
confirmed)
Hospitalised patients where CR infection has been confirmed and cefiderocol is
best option based on pathogen susceptibility information and/or where other
treatment choices are inappropriate (efficacy, contra-indication or tolerability).
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OVERVIEW OF PRE-CLINICAL AND CLINICAL EVIDENCE
Unlike other therapeutic areas, the evaluation of the effectiveness of an antibacterial relies on
the combined consideration of in vitro, Pharmacokinetic (PK)/Pharmacodynamic (PD) and
clinical data. Cefiderocol’s favourable in vitro minimum inhibitory concentrations (MICs)
correlate well with in vivo efficacy in PK/PD in vivo efficacy in validated animal models of
infection, including MDR pathogens. Randomized clinical trials in patients with complicated
urinary tract infections (cUTI) [51], nosocomial pneumonia (HAP/VAP/HCAP), and BSI have
provided confirmation of the good efficacy and safety of cefiderocol in key target patient
populations.
In vitro evidence shows cefiderocol has activity in >95% of CR Gram-negative isolates
In vitro activity of cefiderocol has been studied in two large surveillance studies (SIDERO-
WT/Proteeae and SIDERO-CR 2014/2016) [29, 30, 45, 46] and many country specific smaller
similar studies. The SIDERO-WT study tested the in vitro antibacterial activity of cefiderocol
against Gram-negative bacteria [29]. A total of 30,459 clinical isolates of Gram-negative bacilli
were systematically collected from USA, Canada, and 11 European countries between 2014
and 2017. Cefiderocol demonstrated activity against 99.5% of Gram-negative isolates at a
MIC of 4 mg/L. Isolates were less susceptible to the comparators including colistin (95.5%),
ceftazidime-avibacatam (90.2%) and ceftolozane-tazobactam (84.3%).
In the SIDERO-CR-2014-2016 study [30], which was a global study of 52 countries, focusing
only on CR isolates, cefiderocol demonstrated potent in vitro activity at a MIC of 4 mg/L against
96.4% of isolates of carbapenem-nonsusceptible pathogens including all of the WHO priority
pathogens and Stenotrophomas maltophilia. Cefiderocol was found to provide a wider Gram-
negative coverage, and more potent in vitro antimicrobial activity than comparators including
ceftazidime/avibactam (39.8%), ceftolozane/tazobactam (37%), and colistin (91.5%).
PK/PD studies predict (probability >90%) that the dosing regimen achieves a
concentration of free drug in plasma > MIC for 75% dosing period
As for other cephalosporins, %fT>MIC is the best predictor of efficacy for cefiderocol. A dosing
regimen delivering 75% T>MIC succeeded achieving at least 1 log10 kill reducing the number
of viable bacterial cells in both murine thigh infection and murine lung infection by at least 90%
regardless of the isolate used to induce the infection (E. coli, K. pneumoniae, P. aeruginosa,
A. baumannii or S. maltophilia).
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A 3-compartment model was used to describe the plasma concentrations of cefiderocol. A 3-
compartment pharmacokinetic population model was developed based on pharmacokinetic
data from healthy volunteers, patients with renal impairment and patients from the clinical
trials. Probability of Target Attainment (PTA) for 75% fT>MIC was above 97% for a MIC of 4
mg/L regardless of the site of infection or the renal function. In the epithelial lining fluid (ELF),
PTA for 75% fT>MIC was above 88% for a MIC of 4 mg/L confirming the adequacy of the
dosing regimen in the different patient populations. The dosing regimen therefore ensures
sufficient drug exposure to maximise the efficacy of cefiderocol.
Evidence from a streamlined clinical trial programme supports the in vitro data
An improved in vitro potency in addition to a well-characterized favorable PK/PD profile are
crucial to achieve both adequate exposure to the antibacterial over the MIC for the pathogen,
and clinical cure in patients infected with drug-resistant pathogens [52]. Therefore, clinical
studies in antimicrobials, provide only supportive safety and efficacy evidence to the pivotal in
vitro and PK/PD data. Furthermore, in the context of antibacterial resistance, the standard
clinical trial approach aiming at demonstrating superiority over existing treatments is not
feasible. Treatment options for MDR infections do not allow a superiority trial and it would be
unethical to wihthold effective treatment to pateints in such trials [52]. Hence, clinical trials
have an important role to confirm clinical efficacy, but a limited role in providing comparative
evidence outside the trial, as only pathogens that fall within the in vitro spectrum of the tested
treatments and comparators are included in the study. This is particularly relevant for
antimicrobial treatment selection in the absence of antibiogram.
The clinical efficacy and safety of cefiderocol was demonstrated in 2 randomised double-
blinded clinical trials and 1 open label, descriptive study.
The APEKS-NP study compared treatment with cefiderocol against the combination of high-
dose (HD), prolonged infusion meropenem in patients with nosocomial pneumonia caused by
MDR Gram-negative pathogens. Three hundred (300) patients were randomized 1:1 to
cefiderocol or HD meropenem, a regimen only used in more difficult-to-treat pathogens which
optimizes exposure and efficacy for meropenem. Cefiderocol met the primary endpoint of non-
inferiority in all-cause mortality (ACM) at day 14 versus HD meropenem (12.4% for cefiderocol
and 11.6% for HD meropenem; [95 % CI: -6.6, 8.2]) and similar results maintained for ACM at
Day 28 and end of study (EOS). Rates of clinical cure and microbiological eradication at TOC
were also similar between the treatment groups. Although patients with CR-pathogens known
prior to randomization were excluded from the study, in a meropenem-nonsusceptible
subgroup (MIC>8mg/L) later identified, the rates of ACM at Day 14 were 17.1% in the
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cefiderocol group and 20.0% in the HD meropenem group. Adverse events were similar
between cefiderocol and HD meropenem and cefiderocol safety profile was consistent with
other cephalosporins.
APEKS-cUTI was an international, multicenter, randomised, double-blind, active-controlled,
parallel-group, non-inferiority study to investigate the efficacy and safety of cefiderocol vs
imipenem/cilastatin (IPM/CS) in cUTI caused by Gram-negative MDR pathogens in hospitalisd
adults [51, 53]. 448 patients were randomized, of whom 300 received cefiderocol and 148
received IPM/CS. The primary efficacy endpoint was the composite of clinical response and
microbiological response rate at TOC assessment, in the MITT (microbiological Intent-to-treat)
population. The results demonstrated that 73% of patients in the cefiderocol group achieved
the primary endpoint, vs only 55 % of patients in the IPM/CS group, with an adjusted treatment
difference of 18.6% (95 % CI: 8.2, 28.9). This difference showed superiority in favour of
cefiderocol in a post-hoc analysis. Adverse events were similar in type and rate between
treatment groups and cefiderocol safety profile was consistent with other cephalosporins.
A Network Meta-Analysis (NMA) was feasible for cUTI, given the similarity of patients and
pathogens included across trials. All results were consistent with APEKS-cUTI trial and
showed no statistically significant differences compared to ceftazidime/avibactam and
ceftolozane/tazobactam in a similar patient population with similar pathogen distribution.
The CREDIBLE CR study was a small, exploratory, open label, randomised, descriptive study
to evaluate efficacy of cefiderocol and best available therapy (BAT) in critically ill patients with
confirmed CR infections, but was not designed or powered for statistical comparison between
arms. The study included 150 severely ill patients, (48 allocated to BAT) consistent with
compassionate use cases, with a range of infection sites including nosocomial pneumonia,
cUTI, BSI/sepsis. Many patients had end stage comorbidities and had failed multiple lines of
therapy. Clinical and microbiological outcomes were similar between the 2 arms, but there
were marked imbalances in some baseline clinical relevant characteristics and pathogen
distribution of the cefiderocol and BAT arms.
Cefiderocol has proven efficacy in complex compassionate use cases to date
More than 200 patients to date have been treated with cefiderocol within the compassionate
use programme around the world, highlighting the unmet medical need for alternative
antibacterials active against CR Gram-negative pathogens. Confirmed information on 74
patients who have completed treatment in this program showed that over 60% of the severely
ill patients infected with CR Gram-negative pathogens survived when no other treatment
option was available to them.
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In the absence of AST results, cefiderocol is estimated to provide better predicted
susceptibility rates and projected clinical success rates considering the European
Gram-negative pathogen epidemiology
When critically ill patients require immediate treatment in the absence of AST results, the
likelihood of treatment success with cefiderocol and comparators can be predicted through an
effectiveness model based on estimates of pathogen prevalence for the specific site of
infection, combined with pathogen susceptibility results for each infection site (taken from the
SIDERO surveillance studies); relying on the drug’s ability to achieve effective concentrations
at the site of infection. Such methodologies are used when ethical considerations limit the
prospective clinical evaluation of treatments by randomized control trials, i.e. where the risk of
exposing patients to potentially ineffective drugs in a clinical trial setting is too great.
Results from this effectiveness model showed that cefiderocol is expected to have higher
predicted susceptibility rates than comparators across different infection sites in the European
prevalent Gram-negative bacteria, and higher projected treatment success rates in cUTI and
pneumonia. These were consistent with trials results from APEKS cUTI and APEKS NP for
cefiderocol, but not for comparators as it includes pathogens for which they are not
susceptible. This modelling approach highlights the limitations of the existing clinical trials, and
the potential difference for the effectiveness rates, when antimicrobials are used in the
absence of AST.
Cefiderocol presents a safety profile consistent with other cephalosporins
The clinical safety for cefiderocol was established in the three randomised clinical trials,
including 549 treated patients, and showed a similar profile compared to other cephalosporins.
Pooled adverse event analyses showed that there were overall less treatment emergent
adverse events with cefiderocol (344/549 [67.1%]) vs comparators (252/347 [72.6%]), as well
as less treatment related AEs, (56/549 [10.2%]) with cefiderocol vs compartors (45/347
[13.0%]).
In the nosociomial pneumonia study treatment-emergent adverse events (TEAEs) and
treatment-related TAEs were balanced between arms. SAEs 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 and 10.7% in meropenem
group), hypokalemia (10.8% vs 15.3%) and anemia (8.1% vs 8%).
In the cUTI study 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%). The most
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frequently observed AEs were gastrointestinal, such as diarrhoea [experienced by 4.3% and
6.1% of cefiderocol- and IPM/CS-treated subjects, respectively], and there was an numerical
increased incidence of C. difficile colitis in the IPM/CS arm compared with cefiderocol. Serious
adverse events (SAE) occurred less in cefiderocol-treated patients than in IPM/CS-treated
patients (5% vs 8%).
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,
than was observed for patients receiving BAT. The incidence of treatment-related AEs leading
to discontinuation was similar between treatment groups. A blinded adjudication committee
concluded that none of the deaths in the cefiderocol arm was due to a drug-related AE,
although one death due to acute kidney injury in the BAT arm was attributed to colistin-based
therapy. 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 population randomised.
CONCLUSION
Cefiderocol is an innovative, effective and well tolerated treatment for aerobic GN infections
in patients with limited treatment options. Cefiderocol overcomes the common resistance
mechanisms of GN pathogens and covers a broad range of aerobic, GN bacteria including all
three WHO priority CR pathogens (Enterobacteriaceae, A. baumannii and P. aeruginosa) and
the CR Stenotrophomas maltophilia and Burkholderia cepacia. It provides an important
alternative for physician managing patients with MDR/CR infections.
Cefiderocol’s favourable in vitro MICs across all relevant pathogens correlates well with in vivo
efficacy in PK/PD analyses. Randomized clinical trials in patients with cUTI, nosocomial
pneumonia (HAP/VAP/ HCAP), and BSI and sepsis have provided confirmation of the good
efficacy and safety of cefiderocol in key target patient populations, alongside compassionate
use case reports.
The combination of in vitro, PK/PD, and clinical data predicts that cefiderocol has a greater
likelihood of obtaining clinical success rates, in patients with suspected MDR/CR infections
than relevant comparators across different infection sites.
Cefiderocol provides an important new option for treating critically ill, hospitalised patients
where MDR/CR infection is suspected and time to effective treatment must be minimised, and
for patients where an MDR/CR infection has been confirmed and it is the most appropriate
option, due to pathogen susceptibility or where other treatment choices are inappropriate.
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1 Description and technical characteristics of the technology
Summary of the characteristics of the technology
Cefiderocol is the first siderophore cephalosporin [44] to be approved. It’s unique
molecular structure and novel mechanism of cell entry allow it to overcome the three
major resistance mechanisms found in Gram-negative pathogens (i.e., degradation by
β-lactamase enzymes, porin channel mutations and overexpression of efflux pumps):
o Cefiderocol has improved stability to hydrolysis by β-lactamases, including all
4 types of carbapenemases, key enzymes rendering resistance to β–lactam
antibacterials, including carbapenems.
o Cefiderocol exploits the bacteria’s need for iron and mimics the action of
bacterial own siderophores. A chelate complex with free iron is formed, which
is then actively transported into the bacterial cell via iron transporters,
circumventing pathways traditionally used by other antibacterials such as efflux
pumps or porin channels, which bacteria can regulate to reduce their exposure
to antibacterials.
Cefiderocol is active against a wider range of aerobic, GN bacteria than its
comparators (including all WHO priority pathogens: CR Enterobacteriaceae, CR P.
aeruginosa and CR A. baumannii). In addition, cefiderocol is also active against
intrinsically CR Stenotrophomas maltophilia and Burkholderia cepacia.
In Europe, Shionogi seeks a pathogen-focused indication for cefiderocol, and it is
expected to be approved for the treatment of infections due to aerobic GN organisms
in adults with limited treatment options. Within this indication, it is proposed that
cefiderocol offers most value in two clinical scenarios, and evidence for cefiderocol
and its relevant comparators is provided for each:
o Hospitalised patients with suspected (but prior laboratory confirmation)
MDR/CR infection who are critically ill and require immediate antibacterial
treatment that provides full cover against CR pathogens and potential resistant
mechanisms, to avoid the risk of rapid clinical deterioration (with the option to
de-escalate to a more targeted treatment when the pathogen and susceptibility
profile is subsequently confirmed).
o Hospitalised patients where CR infection has been confirmed and cefiderocol
is best option based on pathogen susceptibility information and/or where other
treatment choices are inappropriate (efficacy, contra-indication or tolerability).
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Cefiderocol was approved by the U.S. Food and Drug Administration (FDA) on
November 14, 2019, for treatment of cUTI in adult patients with limited or no alternative
treatment options. Based on the results of the recently presented APEKS NP study
Shionogi is preparing a sNDA submission to FDA for approval of cefiderocol for
pneumonia in 2020.
Evaluation of the effectiveness of an antibacterial requires the integrated analysis of in
vitro, PKPD and clinical data.
o Two large susceptibility studies, SIDERO-WT/Protea and SIDERO-CR
2014/2016), showed cefiderocol to have activity against 99.5% of GN isolates
and 96.2% of CR GN isolates respectively. This was higher than other tested
antibacterials, according to CLSI breakpoints. This was replicated in several
small country specific studies, with consistency results.
o Cefiderocol’s favourable in vitro MICs correlate well with in vivo efficacy in
PK/PD analyses conducted.
o Three clinical trials (APEK cUTI, APEKS NP and CREDIBLE CR) have
provided confirmation of the efficacy and safety of cefiderocol in key infection
types: cUTI, nosocomial pneumonia (HAP/VAP/HCAP), and BSI.
o In the absence of AST results, and in an integrated effectiveness model
analysis of European pathogen epidemiology, in vitro/in vivo data, and clinical
data, cefiderocol provides the best predicted susceptibility rates and projected
clinical success rates considering for the EU setting.
Cefiderocol provides an important new option for treating critically ill, hospitalised
patients where MDR/CR infection is suspected and time to effective treatment must
be minimised, and also for patients where an MDR/CR infection has been confirmed
and it is the most appropriate option, due to pathogen susceptibility or where other
treatment choices are inappropriate
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1.1 Characteristics of the technology
1. In Table 1 provide an overview of the technology.
Table 1: Features of the technology
Non-proprietary name Cefiderocol
Proprietary name FETCROJA
Marketing
authorisation holder
Shionogi B.V., Amsterdam, Netherlands
Class Antibacterials for systemic use
Active substance(s) Siderophore cephalosporin
Pharmaceutical
formulation(s)
Powder for concentrate for solution for infusion (powder for concentrate).
White to off-white powder.
ATC code J01DI04 cefiderocol
Mechanism of action Cefiderocol is a siderophore cephalosporin. In addition to passive
diffusion through outer membrane porin channels, cefiderocol can bind to
extracellular free iron via its siderophore side chain, allowing active
transport into the periplasmic space of Gram-negative bacteria through
siderophore uptake systems. Cefiderocol subsequently binds to penicillin
2.1.4 Risk and prognostic factors for MDR and CR infections
2.1.4.1 Risk factors
Risk factors for CR Gram-negative infections consist of a combination of patient clinical
setting/healthcare exposure and patient-level characteristics [115-117] and include risk factors
that are common to all nosocomial infections (e.g. long term hospitalisation, invasive
procedures, long-term ventilation, or depressed host immune system), and some are more
specific to CR infections (e.g. previous colonization or infection with CR pathogen, prior
exposure to carbapenems, and recent hospitalisation in a endemic CR infections country, or
where there was a recent outbreak). Risk factors can vary by infection site (e.g. ventilation is
more frequently reported in pneumonia). [85, 118-122].
A summary of the most commonly reported risk factors according to different pathogens is
included as an appendix [123] (see Table 6.1:Most commonly reported risk factors per
pathogen).
2.1.4.2 Prognostic factors
Time to effective therapy impacts patient’s overall outcomes. Delays in the determination of
the pathogen identity and AST results frequently lead to inadequate initial treatment, which
causes increased morbidity and mortality. The impact of treatment delay of appropriate
treatment was analysed in an SLR [124, 125] reviewing 145 studies and considering three
types of outcome comparisons: delay vs. no delay in receiving appropriate therapy, duration
of delay of appropriate therapy, and appropriate vs. inappropriate initial therapy. A delay in
patients receiving appropriate effective treatment was shown to lead to worse patient
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outcomes, including higher mortality rates. Early treatment with appropriate initial therapy
represents an important prognostic factor in the treatment of patients with GN infections with
limited treatment options. This is further detailed in this section
2. Present an estimate of prevalence and/or incidence for the disease or health condition
including recent trends.
2.1.5 Epidemiology
The rate of infections caused by multidrug-resistant (MDR) bacteria continues to increase and
limit the utility of existing antibacterial agents. In its surveillance report (2018), 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 [126]. 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 infection [4].
Carbapenem-resistance (CR) in Pseudomonas aeruginosa, Klebsiella pneumoniae and
Acinetobacter spp. contributed significantly to the number of estimated deaths (in total
approximately 9,000 deaths).
Reports on CR isolates are highly heterogeneous across the globe (Figure 8), 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 [127, 128].
Figure 8: Worldwide carbapenem resistance
Source: CDC 2013[80]; ECDC 2017[79]; Mendes et al.[129]; Kiratisin et al.[130]
In the EU-5, the number of CR Gram-negative infections has been reported to be 65,592 in
2015, 123,069 in 2018 and 124,630 in 2019 with P. aeruginosa and A. baumannii as the most
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frequently diagnosed CR pathogens [4, 79, 111]. Across EU-5 countries, prevalence of CR
Gram-negative infections is reported to range between 0.14 per 100,000 in the UK to 3.05 per
100,000 in Italy (Figure 9) [4].
Figure 9: Prevalence of CR Gram-negative infections in the EU-5
Source: Cassini, 2018[4]
Prevalence estimates are available from multiple sources, generated thorugh different
methodologies. Furthermore, pathogen resistance is a constantly evolving, and therefore,
results may vary significantly with time, and region/country. Also relevant to account is the fact
that the epidemiology varies across the different pathogens, and infections sites:
Non-fermenters P. aeruginosa and Acinetobacter spp. are the most common
pathogens. P. aeruginosa was found in 17% to 61% of CR infections and
Acinetobacter spp. in 19% to 50%. The second most common CR pathogen is K.
pneumoniae (6% to 20% of infections) followed by E.coli (0.1% to 2.8%) [4, 79, 111].
The most prevalent CR Gram-negative infection site is the respiratory tract with
reported ranges from approximately 41% [4] to 57%[111], followed by UTI and
BSI/Sepsis (Table 7).
Table 6: Most common CR causal pathogens across available EU-5 data sources
Pathogen % of causal pathogen for CR Gram-negative infections
P. aeruginosa 17%-60.7%
A. baumannii 19%-50%
K. pneumoniae 6%-20.0%
S. maltophilia 1%a
E. coli 0.1%-2.8%
1,20
0,31
3,05
0,64
0,14
1,07
France Germany Italy Spain UK EU-5 average
Cases/100,000
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A proportion of S. maltophilia that caused HAIs Suetens 2018[106]
Sources: ECDC 2018[79]; Cassini et al, 2018[4] and DRG 2017[111]
Table 7: Proportion of CR infection sites in the EU-5
Infection site % of infection sites for CR Gram-negative infection
Respiratory tract 41.3%-57%
Urinary tract 17.0%-19.1%
Bloodstream 11.2%-21%
Abdomen 2.0%
Skin/wound 10.7%-12.8%
Other 7.8%
Sources: Cassini et al, 2018[4] ; DRG 2017[111]
While there appears to be geographical variation in different types of carbapenemases, recent
surveillance study reports an overall increase in these enzymes.
While carbapenem resistance affects both non-fermenters and fermenters in all regions,
mechanisms of resistance appear to vary geographically [48, 128].
Analyses from SIDERO-CR surveillance studies [131] confirmed the diversity in
carbapenemases across Europe, reporting prevalences of carbapenemas producing
Enterobacteriaceae (CRE), P. aeruginosa (CRP), and A. baumannii (CRA) (Figure 10).
Overall there is an increase in the prevalence of isolates with carbapenemases with significant
divrsity (Figure 11) [103] and non-carbapenemase mechanisms of resistance are present in a
significant proportion of isolates, particularly in E. coli. (Figure 12) [103, 132]
Figure 10: Epidemiology of carbapenemases in EU 5
Source: Shionogi data on file (Data adapted from SIDERO-CR study)[131]
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Figure 11: Confirmed carbapenemase-producing Enterobacteriaceae isolates (Public Health
England: 2008–17)
Source: ESPAUR, 2019[132]
Figure 12: Distribution of carbapenem resistance mechanisms in Enterobacteriaceae species in
the Europe
Source: Nordmann, 2019 [128]
3. Describe the symptoms and burden of the disease or health condition for
patients.
Multi Drug Resistant Gram-negative infections primarily occur in vulnerable hospitalized
patients. These pateints are often ≥ 50 years of age, severely transplanted patients, possibly
in intensive care units (ICU), or undergoing chemotherapy, or patients who have compromised
immunogenicity, and generally wuth multiple comorbidities (e.g. heart disease, diabetes or
kidney disease) [68, 69].
The clinical burden of bacterial infection has an impact on key outcomes such as longer
treatment, extended hospital admission, additional healthcare professional time, healthcare
resource use, adverse events, greater disability (morbidity) and increased risk of death
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(mortality) [76]. The need to treat patients empirically before pathogen susceptibility has been
confirmed means that this initial treatment choice in MDR is often inappropriate and this can
have a significant impact on the individual patient due to the negative clinical consequences
of a delay on effective treatment [133, 134].
An overview of signs and symptoms of common CR infections by infection site is provided in
Table 8.
Table 8: Overview of disease burden according to the infection site
Site of infection Signs and Symptoms2 Mortality
pneumonia Dyspnoea a Productive cough a Fever a Chest pain a Loss of appetite a
5,495 annual number of deaths in Europe due to ICU-acquired
pneumonia (2008–12)[108]
Attributable mortality rate: ~3.5%
cUTI Fever b Increased urinary frequency b and urgency b Haematuria b Dysuria b Suprapubic/flank pain b
Can develop bacteraemia and sepsis in 10% to 30% of cases,
with risk of death reaching up to 40%[109, 110]
BSI Fever c Chills c Tachycardia c Tachypnoea c Potential complications: Infective endocarditis d Osteomyelitis d Infectious arthritis d Septic shock/sepsis d
4,505 Annual number of deaths in Europe due to ICU-acquired
bloodstream infections (2008–12) [108]
Attributable mortality rate: ~5%
sepsis Dyspnoea e Confusion e Tachycardia e Fever/shivering/feeling very cold e Extreme pain e Clammy/sweaty skin e
A rate of hospital mortality for sepsis: 17%-26% in severe cases
[135]
Extrapolation to global estimates: ~ 5.3 million deaths annually
from sepsis
cIAI Fever f Tachycardia f Tachypnoea f
Hypotension f Abdominal pain f Nausea and vomiting f Diarrhea f Abdominal fullness e Obstipation e
Severe infections: mortality rate of 30-50%
In case of sepsis: mortality rate > 70%g
Sources: a. https://www.blf.org.uk/support-for-you/pneumonia/symptoms ; b. Sabih et al, 2019[136]; c. MedlinePlus -
Medical Dictionary[137] d. Hassoun et al, 2017 [138];
Symptoms of MDR (including CR) Gram-negative infections vary according to the infection
site, but for the same infection site, are no different than that caused by other serious
infections.
2 Symptoms of MDR (including CR) Gram-negative infections do not differ from those of other serious
infections.
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2.1.6 Mortality
Multidrug resistant infections, including CR, are associated with 1.6 to 5.0 times higher
mortality risk compared non-MDR/CR infections [21, 139, 140]. Mortality rates can reach up
to 70% in the most severe cases such as bacteraemia [141]. In Europe, the mortality
associated with MDR and CR Gram-negative infections is estimated to be 35% [142-148] .
The extent of the clinical burden of infections with Gram-negative pathogen depends on the
severity of infection but generally the burden increases when coinciding with resistant
pathogens. The risk of mortality is more than doubled when the cause of an infection is MDR
Gram-negative bacilli, in comparison to susceptible organisms [134] For carbapenem-
resistant Gram-negative infections, mortality has been estimated to range between 26-44% in
one meta-analysis [149], and between 30-75% in another review of studies [150].
Clinical outcomes and burden from Gram-negative bacterial infection can vary depending on
the site of infection:
HAP/VAP: Mortality rate estimates in patients with pneumonia ranged from 48.6% to 64.7%
[115]. The crude mortality rate associated with VAP has been observed to range from 25% to
76% [151] but mortality directly attributed to VAP could be less than 10% because patients
with VAP are already being treated for life-threatening illnesses and may die from the comorbid
disease [152-154].
BSI: Hospital-acquired BSI has been associated with substantial morbidity and mortality [155,
156]. According to ECDC, patients with BSIs due to carbapenem-resistant Enterobacteriaceae
have mortality rates reaching 50% [157].
In Europe, sepsis caused by the most frequent resistant bacteria is responsible for
approximately 25,000 deaths per year, and that two-thirds of these are due to Gram-negative
pathogens [158].
UTI: Patients with cUTI can develop, in 10% to 30% of the cases, bacteraemia being
associated with a mortality rate ranging between 30% and 40% [110].
The clinical burden of Gram-negative bacilli infections varies depending on the causal
pathogen. Infection by Gram-negative pathogens, and specifically MDR Gram-negative
pathogens such as E. coli, K. pneumoniae, P. aeruginosa, and Acinetobacter spp. can result
in significant clinical burden due to the increase in the length of hospital stay, lack of clinical
efficacy, treatment-related adverse events, morbidity and mortality. The reported hospital
mortality rates were highest for A. baumannii (23.4 to 50%) and P. aeruginosa (50 to 59.5%),
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followed by K. pneumonia (14.4 to 24%) and E. coli (2.5%) [115] [159] [160] [142, 161].
However, quantifiable research at the pathogen level is limited and influenced by global
variation in epidemiology, small study sizes and varying definitions of resistance to
antimicrobials, leading to difficulties with cross-pathogen comparisons of the pathogen-
specific impact of an AMR Gram-negative infection.
Patient factors such as health status and functional status can further contribute to the clinical
burden of Gram-negative infection. Mortality associated with CR infections can reach up to
100% in severe cases such as mechanically ventilated patients with bacteraemia [115]. In
addition, admission to a hospital with a high prevalence of MDR Gram-negative pathogens
and inpatient stay due to invasive procedures (e.g. surgery, ventilators, catheters) increases
the risk of infection and thus the risk of poor clinical outcome if the procedure [134].
2.1.7 Quality of Life
There is limited and confounded information available on the impact of infections over the
quality of life of these patients, as these are severely ill patients who are frequently treated in
ICU units and may be intubated and unconscious, and unable to complete these
questionnaires. The quality of life of these patients is also impacted by their underlying
disease, and most importantly by the severity of the infection and the infection site (i.e. patients
with BSI and sepsis are expected to have lower quality of life compared to a patient with cUTI).
The fact that these patients are hospitalised already has detrimental impact on their quality of
life. The ward in the hospital also impacts the patient’s quality of life (i.e. patients on ICU or
isolation, are expected to have lower quality of life compared to general ward), although this
may be correlated with the severity of the infection and underlying condition. All these factors
make investigating quality of life in antimicrobial clinical trials difficult and infrequent. However,
any therapy that resolves the infection and/or reduces length of hospitalization is expected to
improve patient’s quality of life.
2.1.8 Disability Adjusted Life Years (DALYs)
The estimated burden of infections with antibacterial-resistant bacteria in Europe is substantial
compared with that of other infectious diseases [4]. A study based on EARS-Net data from
2015 estimated that infections due to antibacterial-resistant bacteria3 accounted for 33,110
attributable deaths and 874,541 DALYs [4]. Infections with colistin-resistant or CR pathogens
The included antibacterial resistance-bacterium combinations were colistin-resistant, carbapenem-resistant, or multidrug-resistant Acinetobacter spp; vancomycin-resistant Enterococcus faecalis and Enterococcus faecium; colistin-resistant, carbapenem-resistant, or third-
generation cephalosporin-resistant
Escherichia coli; colistin-resistant, carbapenem-resistant, or third-generation cephalosporin-resistant Klebsiella pneumoniae; colistin-resistant, carbapenem-resistant, or multidrug-resistant Pseudomonas aeruginosa; meticillin-resistant
Staphylococcus aureus (MRSA); and penicillin-resistant and macrolide-resistant Streptococcus pneumoniae
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accounted for 38.7% of the total DALYs. The highest burden in terms of lost DALYs and deaths
was noted in Italy and Greece.
The burden due to DALYs associated with antibacterial-resistant bacteria including CR and
colistin-resistant infections is reported to have increased between 2007 and 2015. The
proportion of the DALYs due to all CR infections increased from 18% in 2007 to 28% in 2015.
With regards to specific pathogens, the proportion of the DALYs due to CR K. pneumoniae
and CR E. coli doubled from 4.3% in 2007 to 8.79% in 2015.
In terms of infection sites, the highest DALYs burden was associated with BSI reaching up to
71,201 DALYs, and with respiratory infections, reaching up to 19,132 DALYs. The main CR
pathogen contributing to DALY was P. aeruginosa except in Italy, where the most burdensome
pathogen was K. pneumoniae. The annual number of DALYs attributable to P. aeruginosa
ranged from 1,576 to 34,717. In Italy, CR K. pneumoniae was associated with 37,394 DALYs.
2.1.9 Delayed effective therapy
Given that conventional pathogen identification and AST results can take up to 3 days to
provide a diagnostic result, the current treatment approach for patients with bacterial infections
suspected to be caused by an MDR pathogen, involves initial administration of empiric therapy
with wider-spectrum of activity antimicrobial followed by de-escalation to targeted therapy
when AST results are available [13, 14]. However, in many instances, the antibiogram is not
retrieved. The Point prevalence survey of healthcare-associated infections and antimicrobial
use in European acute care hospitals 2011–2012 indicated that between 40.2% and 80.5% of
HAIs are documented with microbiological results [11]. The percentage of pathogens with
known AST results is reported to vary between 47.4% and 100% [11].
Increasing antibacterial resistance has made the empiric antibacterial selection more difficult
particularly as fewer appropriate treatments for resistant pathogens are available [162]. As a
result, many patients with severe bacterial infections receive inappropriate therapy and
consequently experience delays in receiving appropriate effective therapy. As the severity of
infection increases, patients are more likely to be cycled through a number of inappropriate
therapies in the attempt to successfully treat the infection. According to two recent systematic
literature reviews ((1) 2015, n=27 and (2) 2019, n=122), patients receiving inappropriate
empiric treatment were reported to have a higher mortality risk [163, 164].
A systematic literature review including studies on the incidence and outcome of
inappropriate in-hospital empiric antibacterials for severe infections published
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between 2004 and 2014 reported that the percentage of inappropriate empiric
antibacterial treatment ranges between 14.1% and 78.9% [163].
A retrospective cohort study including 40,137 patients with Enterobactereacea in
UTI, pneumonia or sepsis reported that patients with CR Enterobactereacea
(CRE) were three times more likely to receive inappropriate empiric treatment
(IET) than non-CRE (46.5% vs. 11.8%, p < 0.001) [165].
A systematic literature review (2007-2018, n=37) assessing the impact of delay in
appropriate antibacterial therapy for patients with severe bacterial infections
treated in hospital settings concluded that approximately 27% of patients
experience delays [166].
A delay in effective treatment of an infection may lead to sepsis, a life-threatening condition,
irrespective of the initial infection site. A range of studies have confirmed that inappropriately
treated patients had 5-times higher mortality risk, twice longer hospital stays and increased
risk of readmission, compared to patients receiving appropriate initial therapy. Moreover,
patients who fail initial therapies and reach last resort antibacterials are exposed to additional
burden associated with severe adverse events and toxicity [167].
In a more recent (2019) systematic literature review, Bassetti et al reported significantly lower
mortality rates in patients with appropriate therapy compared to those with inappropriate
therapy (OR 0.44 [95% CI, 0.39–0.50]) and these findings were consistent across all time
points (Figure 13) [164]. In a pooled subgroup analysis, mortality rates were significantly lower
in patients with bacteraemia, sepsis and septic shock in patients with pneumonia who had
received appropriate therapy compared to those having inappropriate treatment [164]. This
burden increases with resistant pathogens, whereby patients with CR P. aeruginosa infections
who receive initial inappropriate treatment have mortality risk that is twice as high as that seen
in susceptible patients (27.3% vs 13.8% respectively) [15].
In another recent systematic literature review of 37 studies by Zasowki et al. (2019), patients
2.3.1 Key information on currently available treatments in Europe
As outlined before, treatment options for infections with MDR/CR aerobic Gram-negative
pathogens are very limited. Susceptibility tests have shown that to date broad coverage,
including pathogens affecting patients with limited treatment options (such as CR A.
baumannii, CR P. aeruginosa, S. maltophilia, and CR Enterobacteriaceae) is only achieved
by cefiderocol [29, 30]. In a recent analysis of the global clinical antibacterial pipeline by WHO,
cefiderocol was reported to be the only antibacterial providing coverage against all three
critical priority pathogens: CR A baumannii, CR P aeruginosa, and CR Enterobacteriaceae
(Figure 7) [64].
Ceftazidime/avibactam is a recently approved combination of a well-known beta-lactam with
a novel β-lactamase inhibitor for cIAI, cUTI, HAP/VAP and aerobic Gram-negative infections
in adults with limited treatment options (EU)[178]. It is active against class A (e.g., KPC) and
class D (e.g., OXA) carbapenemase-producing CRE and has demonstrated activity against
some CR P. aeruginosa isolates [177]. Recent results of in vitro study, SIDERO-WT, reported
CRE
• Ceftazidime/avibactam (as preferred empiricalchoice when both KPC and OXA carbapenemases are reported locally) or meropenem/vaborbactam
• Although in the lack of high-level evidence, for both empirical and targetedtreatment a combination with old (collistin, polymyxin B, tigecycline, oldaminoglycosides, fosformycin) or novel agents (plazomicin, eravacycline, double BL-BLI combinations) could be considered in the attempt of delayig emergence ofrestistance, after having carefully balanced potentional additional toxicity on a case-by-case basis (expert opinion)
• In case of resistance to novel BL-BLI, consider polymyxins-based or aminoglycosides-based combination with carbepenems and/or (tigecyclineor eravacycline) and/orfosformycin
• Consider concomitant adminitration of inhaled polymyxins/aminoglycosides whenthey are used intravenously for VAP
• Ceftolozane/tazobactam (as preferred empirical choice in absence of concomitantrisk of CRE) or ceftazidime/avibactam
• For empirical therapy, administer a second anti-pseudomonal agent (an aminoglycosideor a polymyxin or fosformycin)
• Although in the lack of high-level evidence, for targeted therapy combination withold (collistin, polymyxin B, old aminoglycosides, fosformycin) or novel agents(plazomicin, double BL-BLI combinations) could be considered in the attempt ofdelaying emergence of restistance, after having carefully balanced potential additional toxicity on a case-by-case basis (expert opinion)
• In case of restistance to novel BL-BLI, consider polymyxins-based or aminoglycosides-based combinations with carbapernems and/or fosformycin and/or rifampin
• Consider concomitant administration of inhaled polymyxins/aminoglycosides whenthey are used intravenously for VAP
CRPA
CRAB
• Administer a polymyxin as the backbone agent• Consider combination with old (carbapenems, old aminoglycosides, tigecycline,
fosformycin, rifampin) or novel agents (plazomicin, eravacyclin)• Consider concomitant administration of inhaled polymyxins/aminoglycosides when
they are used intravenously for VAP
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a poor activity of ceftazidime/avibactam against CR A. baumannii with minimum inhibitory
concentration (MIC50) for meropenem-non-susceptible A. baumannii of 32 mg/L3 [46] and
stenotrophomonas maltophilia. Currently widely available on the EU countries, with
reimbursement.
Ceftolozane/tazobactam is a novel combination of a beta-lactam antimicrobial with a well
known β-lactamase inhibitor, with EMA approval for cIAI and cUTI [179]. It has demonstrated
a potent in vitro activity against CR P. aeruginosa isolates; however, without activity against
CRE [177]. Tazobactam (β-lactamase inhibitor) protects ceftolozane from degradation by
Class A β-lactamase enzymes [179], but has not demonstrated activity against KPC Class A
carbapenemases, and Class B (metallo-), or Class D β-lactamases [179]. Currently widely
available on the EU countries, with reimbursement.
Meropenem/vaborbactam is a novel combination of a well know carbapenem in a higher
dose, and a novel β-lactamase inhibitor approved for cIAI, cUTI, HAP/VAP, and infections due
to aerobic Gram-negative organisms in adults with limited treatment options [180]. It has
activity against class A (e.g., KPC) carbapenemase-producing CRE. Vaborbactam has limited
activity against Class D β-lactamases and no activity against Class B (metallo-) β-lactamases
and does not improve the activity of meropenem against CR A. baumannii, P. aeruginosa or
S. maltophilia [181]. However, is it not yet reimbursed in most of the European markets.
Currently approved by EMA, but not yet reimbursed in many countries and therefore, not
widely available on the European countries.
Eravacycline is a novel synthetic fluorocycline that was approved by EMA for the treatment
of cIAI [182]. It has demonstrated activity against Gram-negative pathogens including CRE
and CR A. baumannii with exception of P. aeruginosa and Burkholderia cepacia [177, 183,
184]. Currently approved by EMA, but not yet reimbursed in many countries and therefore, not
widely available on the European countries.
While colistin once was abandoned due to the high rates of renal toxicity in recent years, the
increasing emergence of MDR Gram-negative bacteria appears to have led to its
reintroduction in clinical practice [102]. Colistin has antibacterial activity against a wide variety
of Gram-negative pathogens including E. coli, Klebsiella spp., Enterobacter spp., P.
aeruginosa, and Acinetobacter spp. [185]. Some Gram-negative pathogens such as Proteus
spp., Providencia spp. and most isolates of Serratia spp. are intrinsically resistant to colistin
[185]. While it covers a broad spectrum of Gram-negative pathogens, colistin is associated
with severe adverse events [102, 134]. Among the more severe adverse events are
neurotoxicity, nephrotoxicity, and ototoxicity [102, 134]. Renal failure is reported to reach up
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to 60% in patients treated with colistin[186]. A recent systematic literature review (n=224)
including data on 33,573 patients reported that the overall rate of nephrotoxicity in patients
treated with polymyxins was 0.277 (95% CI: 0.252, 0.303). Nephrotoxicity rates were found to
differ between patients treated with CMS, colistin and PMB (0.260 [95% CI: 0.216, 0.30]),
Given the important role of in vitro surveillance studies for antibacterials, an assessment of
cefiderocol needs to be based on a combination of comparisons of surveillance data and
clinical evidence, as outlined below (Table 12).
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Table 12: Cefiderocol assessment
Population Comparator Data source Result (cefiderocol vs. comparator)
Suspected MDR/CR
High dose Meropenem SIDERO WT surveillance
Broader coverage of Gram-negative, aerobic pathogens. Lower MIC value and preserved efficacy in the presence of carbapenemases.
APEKS-NP RCT
Non-inferior with regard to mortality (primary outcome) and all clinical and microbiological secondary outcomes.
High dose Meropenem Ceftalozane-tazobactam, Ceftazidime-avibactam
Integrated epidemiology and in vitro data analysis
Cefiderocol presents higher weighed susceptibility rates in cUTI, pneumonia, BSI, and gastrointestinal samples vs comparators
High dose Meropenem Ceftalozane-tazobactam, Ceftazidime-avibactam
Effectiveness model integrating epidemiology, in vitro data and clinical data
Cefiderocol presents higher likelihood of clinical and microbiological effectiveness in pneumonia and cUTI vs comparators.
Imipenem/Cilastatin APEKS-cUTI RCT
Non-inferior to comparator, but proven superiority in a post-hoc analysis, on the primary endpoint of combined microbiological eradication / clinical cure at TOC, and secondary endpoint microbiological eradication at TOC.
In similar patient populations with similar pathogen distribution across different trials, and consistent with APEKS-cUTI there was statistical significant difference in microbiological eradication at TOC vs Imipenem/cilastatin, but in all other endpoints there was no statistically significant difference, including clinical cure rates and adverse events
Ceftolozane/tazobactam SIDERO WT surveillance
Lower MIC90 (0.25 vs. 8 for Pseudomonas, 0.25 vs. 32 for Acinetobacter, 1 vs. 64 for Enterobacteriaceae)4 Higher % isolates susceptible to cefiderocol
Ceftazidime/avibactam SIDERO WT surveillance
Same MIC90 for Enterobacteriaceae (1 vs. 1), otherwise superiority of cefiderocol Higher % isolates susceptible to cefiderocol
Confirmed CR
Colistin-based (combination) regimens (most relevant for for A. Baumanii, S. maltophilia,
SIDERO CR surveillance
Higher % isolates susceptible to cefiderocol; Similar in vitro efficacy. Colistin is known to have severe side effects, especially kidney toxicity. Resistances against colistin have
4 Longshaw et al., 2019 ID Week
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pathogens with metalloβ-lactamases)
been reported to increase in epidemiological studies.
Ceftolozane/tazobactam (most relevant for P. aeruginosa, except pathogens with metalloβ-lactamases)
SIDERO CR surveillance
Higher percent susceptibility for cefiderocol against Acinetobacter and Pseudomonas across all included countries (MEM-NS pathogens)5
Ceftazidime/avibactam (most relevant for Enterobacterales, except pathogens with metalloβ-lactamases)
SIDERO CR surveillance
Higher percent susceptibility for cefiderocol against Acinetobacter and Pseudomonas across all included countries (MEM-NS pathogens)
Best available therapy (BAT), predominantly (combination) regimens (most relevant for A. Baumanii, S. maltophilia, pathogens with metalloβ-lactamases)
CREDIBLE-CR Descriptive results only. Evidence of eradication of resistant pathogens. Numerical, non-significant disadvantage with regard to mortality for cefiderocol compared to BAT.
The important question, raised during the scoping process, was: Given the large amount of
heterogeneity in the treatment recommendation and the limited number of comparators in the
surveillance data and the clinical studies, how can clinicians determine when to use
cefiderocol over another potential candidate?
The answer combines the intended label with the target populations, as follows:
The indication for cefiderocol is expected to be:
Fetcroja is indicated for the treatment of infections due to aerobic Gram-negative
organisms in adults with limited treatment options.
This indication will therefore be pathogen focused, not restricted to any specific site of infection
and supports the use of cefiderocol in two types of patients:
Hospitalised patients with suspected (but prior laboratory confirmation) MDR/CR
infection who are critically ill and require immediate antibacterial treatment that
provides full cover against CR pathogens and potential resistant mechanisms, to avoid
the risk of rapid clinical deterioration (with the option to de-escalate to a more targeted
treatment when the pathogen and susceptibility profile is subsequently confirmed).
Hospitalised patients where CR infection has been confirmed and cefiderocol is best
option based on pathogen susceptibility information and/or where other treatment
choices are inappropriate (efficacy, contra-indication or tolerability).
5 Sato et al. 2019 ID Week
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Thus, clinicians will encounter three types of patients in their clinical practice that would be
treated according to the identified guidelines:
1) Patients with infections for which there are sufficient treatment options
listed in the guidelines. These fall out of the scope of the cefiderocol
label and are thus not relevant for the current assessment.
2) At the other end of the spectrum, patients with confirmed MDR/CR
infections, for which the antibacterial susceptibility test shows that
there are no other options but cefiderocol. These patients would gain
an important new, last-resort option with cefiderocol.
3) Patients with suspected MDR/CR options, for which local surveillance
data indicate that many of the currently available comparators will not
provide cover against certain possible carbapenem-resistant
pathogens, and who are critically ill and at risk of clinical deterioration.
These patients would gain a new treatment option to reduce the risk
of insufficient pathogen coverage leading to a delay in appropriate
treatment and consequent clinical deterioration
The clinician could optimize the chances of success by considering different treatment options
based on their indications, the MICs and breakpoints published by EUCAST, and the
outcomes in trials of susceptible patient populations. Based on the local epidemiology, the
clinician would then select an agent (or combination of agents) that would maximize the
likelihood to cover the suspected pathogen.
All this data was integrated into an effectiveness model, where European epidemiological data
for MDR pathogen prevalence rates for specific infection sites was used alongside with results
from the SIDERO surveillance studies, and clinical cure rates from clinical trials, to estimate
the likelihood of success of cefiderocol compared with the most relevant comparators.
The results indicate that cefiderocol would have the highest likelihood of success of clinical
cure and microbiological eradication at these infection sites. For more information please see
section 5.4.1 and 5.4.3
These calculations would have to be adjusted for individual cases by taking into account local
variability of pathogen frequencies, but the approach illustrates a practical solution for the
complex challenge of optimizing treatments in patients with suspected MDR/CR infections.
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Once the antibacterial susceptibility test becomes available, doctors should again follow the
guideline recommendations and de-escalate the treatment to the choice with the narrowest
and specific spectrum for the identified pathogen.
In summary, the combined consideration of international guidelines, the growing unmet need
of antimicrobial resistance, the fact that delays in appropriate treatment cause worse
outcomes, indicate that cefiderocol constitutes a valuable addition to the current treatment
landscape of Gram-negative pathogens for patients with limited treatment options.
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3 Current use of the technology
Summary of issues relating to current use of the technology
Cefiderocol is not yet approved in Europe with the only current use being in
compassionate use programmes. Over 200 patients globally were treated to date under
the compassionate use programme of cefiderocol, underlining the clear unmet need in
patients with highly resistant infections with no treatment options.
o The criteria for fulfilling these requests are highly restrictive. All other available
treatments must be ruled out through susceptibility testing and/or where there is
evidence of treatment failure (efficacy or safety).
o In addition, patients must be unable to enrol in clinical studies of cefiderocol.
Case reports for three patients in the compassionate use programme have been
published.
o A patient was treated successfully for endocarditis due to extensively drug resistant
(XDR) Pseudomonas aeruginosa.
o A patient with multiple comorbidities and a complicated intra-abdominal infection
(IAI) due to MDR Pseudomonas aeruginosa was released from hospital care within
six weeks of completion of cefiderocol treatment.
o A patient with VAP and BSI caused by XDR Acinetobacter baumannii and
carbapenemase-producing Klebsiella pneumoniae had potentially serious organ
failure from older anti-infectives. Six weeks after cefiderocol administration, chest
X-rays showed complete resolution of infection.
An abstract submitted (not accepted) for ECCMID 2020 summarizes results from a case
series of seven severely ill patients with CR Acinetobacter infections treated with
cefiderocol. The two patients who died had received cefiderocol for only two days prior to
death.
While the compassionate use program is restricted to the use of cefiderocol for the
treatment of XDR infections with no other options, the EMA-approved indication will be
broader and encompass early targeted treatment of suspected MDR/CR/difficult-to-treat
infections in addition to treatment of confirmed resistant pathogens.
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3.1 Current use of the technology
1. Describe the experience of using the technology, for example the health conditions
and populations, and the purposes for which the technology is currently used. Include
whether the current use of the technology differs from that described in the (expected)
authorisation.
Since cefiderocol is currently not approved in Europe, the only use has been within the
compassionate use program. This program is registered in https://www.clinicaltrials.gov/
registry under NCT03780140: Expanded Access to Cefiderocol for the Intravenous Treatment
of Severe Gram-Negative Bacterial Infections. Expanded access may be provided for
cefiderocol for qualified patients who have limited treatment options and are not eligible for a
clinical trial.
Case reports for three patients in the compassionate use programme have been published.
o A patient was treated successfully for endocarditis due to extensively drug resistant (XDR)
Pseudomonas aeruginosa.
o A patient with multiple comorbidities and a complicated intra-abdominal infection (IAI) due
to MDR Pseudomonas aeruginosa was released from hospital care within six weeks of
completion of cefiderocol treatment.
o A patient with VAP and BSI caused by XDR Acinetobacter baumannii and
carbapenemase-producing Klebsiella pneumoniae had potentially serious organ failure
from older anti-infectives. Six weeks after cefiderocol administration, chest X-rays showed
complete resolution of infection.
To date over 200 patients have been treated with cefiderocol through this programme.
Detailed information on 74 patients which have completed treatment with cafiderocol are
presented in section 5.4 and are part of the data pacage that substantiates the efficacy of
cefiderocol in patients with confirmed CR infections alongside CREDIBLE CR.
The criteria for compassionate use of cefiderocol are highly restrictive. All other available
treatments must be ruled out through susceptibility testing, and/or there must be evidence of
treatment failure (efficacy or safety). Enrolled patients will have confirmed CR infection and
are likely to be consistent with the target population where patients have confirmed CR
infections. However, EMA-approved indication will be broader and encompass both the
treatment of confirmed resistant infection and patients with infections by suspected MDR
Susceptibility for cefiderocol and the comparators was estimated in different subgroups of
pathogens, suspected MDR/CR infections were defined as pathogens resistant to both
ciprofloxacin and cefepime simultaneously.
Theoretical success in suspected MDR/CR infections was estimated for each antibacterial
agent tested by combining the ECDC Epidemiological data of GN pathogen distribution in
each individual infection site with the susceptibility to each antibacterial agent.
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Table 48 and Table 49 (A-D) below summarize the results of such analyses for four different
infection sites and the respective relevant comparators:
Table 48: Susceptibility to Cefiderocol and comparators in all sites of infections for MDR3
pathogens
Table 49- Theoretical success of antibacterial therapy in Gram‐negative 3MDR pathogens in gastrointestinal site of infections (A) Pneumonia; (B) cUTI; (C) BSI; (D) Gastrointestinal
(A)
(B)
(C)
(D)
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Regardless of the infection sites, cefiderocol demonstrated the highest theoretical success
compared with meropenem, ceftolozane/tazobactam, ceftazidime/avibactam or colistin,for
pre-emptive therapy in suspected MDR/CR infections.
Table 50: Summary table Theoretical percentage of success for Gram‐negative antibacterial
therapy on aerobic Gram‐negative pathogens in different infection type
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5.4.2 Individual study results (PK/PD data, study report S-649266-CPK-004-B)
This section summarizes the methodology, underlying assumptions, and main findings from
extensive population PK/PD modelling efforts for ceficerocol. The full study report of the
PK/PD population model (S-649266-CPK-004-B) is included in the submission.
5.4.2.1 Model description
A population pharmacokinetic (PK) analysis was performed to develop a model using a total
of 3427 plasma concentration data of cefiderocol from the single ascending dose
(SAD)/multiple dose (MAD) study (1203R2111), the renal impairment study (1222R2113), the
phase 2 APEKS-cUTI study (1409R2121), the phase 3 CREDIBLE-CR study (1424R2131),
and the phase 3 APEKS-NP study (1615R2132).
A 3-compartment model was used to describe the plasma concentrations of cefiderocol. The
covariates explored included creatinine clearance calculated by Cockcroft-Gault equation
(CrCL), body weight, age, albumin concentration, aspartate aminotransferase , alanine
aminotransferase, total bilirubin, sex, race, infection (no infection, complicated urinary tract
infection [cUTI] or acute uncomplicated pyelonephritis [AUP] in the phase 2 study, cUTI in the
CREDIBLE-CR study, bloodstream infections/sepsis [BSI/sepsis], either hospital-acquired
Mild: CrCL 60 to < 90 mL/min. Moderate: CrCL 30 to < 60 mL/min. Severe: CrCL 15 to < 30 mL/min. ESRD: CrCL 5 to < 15 mL/min.
PTA for 75% fT>MIC was above 97% for a MIC of 4 mg/L regardless of the site of infection or the renal function. In the ELF, PTA for 75% fT>MIC
was above 88% for a MIC of 4 mg/L confirming the adequacy of the dosing regimen in the different patient populations.
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5.4.3 Retrospective analysis of cefiderocol and comparators by population
PK/PD simulation
A retrospective analysis was performed comparing the probability of target attainment
(PTA) for cefiderocol, ceftolozane/tazobactam and meropenem against
Enterobacterales and Pseudomonas aeruginosa in a representative patient population
at risk of MDR or carbapenem resistant infections. Published pharmacokinetic (PK)
models for meropenem and ceftolozane/tazobactam, and an existing model for
cefiderocol, were used with standard dosage regimens for simulating individual PK
data. The intial list of comparators included ceftazidime/avibactam and colistin, but this
proved not possible to include:
the model implemented for ceftazidime-avibactam could not be appropriately
validated.
the model for colistin, required information about the correlation matrix, and the
nature of the parameter values reported in the original colistin model article,
which was not made available by the original model’s authors.
PTA for clinically relevant pharmacokinetic/pharmacodynamic (PK/PD) targets was
calculated from steady state PK profiles for a range of minimum inhibitory
concentrations (MICs). The calculated PTAs in plasma for the 3 antimicrobials were
above 95% at their respective MIC corresponding to their EUCAST breakpoints
confirming published results. Cumulative fractions of response (CFRs) were also
calculated to estimate using European MIC distributions from the SIDERO surveillance
selected for being resistant to two antibiotic classes (quinolone and cephalosporins)
and thereby representative of a patient population at risk of MDR infections. CFR
analysis was performed on selected European isolates already resistant to cefepime
and ciprofloxacin. In this patient population infected with suspected MDR/CR
pathogens, CFRs were 97.4% and 99.8% for cefiderocol for Enterobacterales and
Pseudomonas spp. respectively. The cumulative fractional responses for cefiderocol
against Enterobacterales and Pseudomonas spp. are considerably higher than seen
for meropenem and ceftolozane-tazobactam. Despite the simulation of high dose,
extended infusion of meropenem CFRs were 91.2% for Enterobacterales but only
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68.4% for Pseudomonas spp. The dose simulated for ceftolozane/tazobactam is also
a high dose applied for the treatment of nosocomial pneumonia however due to the
selected suspected MDR/CR isolates CFRs were only 67.2% for Enterobacterales and
55.2% for Pseudomonas spp.
Table 52. Estimated CFR for MIC distributions corresponding to Enterobacterales and Pseudomonas spp. More simulation results for corresponding PTA, MIC and T>MIC target values are shown in Appendix C. The applied MIC distributions can be seen in Appendix D of the study report.
Cefiderocol Meropenem Ceftolozane-tazobactam*
MIC distribution: Cumulative fraction of response, CFR (%) xxx
Enterobacterales 97.4 91.2 67.2
Pseudomonas spp. 99.8 68.4 55.2
Meaningful comparisons could be made between the performances of the models for
cefiderocol, meropenem and ceftolozane-tazobactam. The simulations showed a
superior performance of cefiderocol against Enterobacterales and Pseudomonas spp
in terms of cumulative fraction of response when compared with meropenem and
ceftolozane/tazobactam (Table 52). It should be noted, though, that the meropenem
model exhibited a very long terminal half-life for the drug in plasma, probably reflecting
that the experimental data originate from a patient population where the majority of the
patients had bloodstream infections.
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5.4.4 Clinical study results (clinical outcomes)
Each section begins with a summary of the results for the respective primary endpoint, followed
by summaries of relevant secondary endpoints in the order shown below. Detailed results (e.g.,
stratifications by pathogen) are provided in 5.4.3 [262, 263]. The section on APEKS-cUTI
contains additional results from a network-meta-analysis.
The Table 53 below summarizes the endpoint analyses requested by EUnetHTA in the scoping
process. In the following sections, the results for each of these endpoints are presented, if
applicable.
EA: early assessment; EOT: end of treatment; TOC: test of cure; FUP: follow up; EOS: end of
study; NR: not relevant; NA: not applicable
Table 53: Endpoint Analysis as per EUnetHTA Request
Study Endpoint/Analysis Available
time points
Stratifi-
cation
by
infection
site
Stratification
by pathogen
Primary
endpoint?
APEKS-
cUTI
Clinical outcome EA, EOT,
TOC, FUP
NA
No. Pathogen
specific data
detailed
results on file
[262]
No
Composite
microbiological
eradication and
cure
EA, EOT,
TOC, and FUP
Yes (at TOC)
Microbiological
eradication
EA, EOT,
TOC, FUP
No
All-cause mortality
at day 14 and 28
NR No
Changes of MIC or
appearance of
resistant bacteria
At EOS
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Network meta-
analysis (NMA)
Clinical Cure
and
microbiological
eradication at
TOC and FU
Not relevant
APEKS-NP Clinical outcome TOC NA
Main
pathogens
No
Microbiological
eradication
EA, EOT,
TOC, FUP
Main
pathogens
No
All-cause
mortality
Day 14, day
28
Yes Yes, day 14
ACM
CREDIBLE-
CR (only
descriptive
results)
Clinical outcome EOT, TOC, FU Yes Main
pathogens
and non-
fermenters
Yes, for
HAP/VAP/HCAP
and BSI/sepsis
Microbiological
eradication
EOT, TOC, FU Yes Yes, for cUTI
All-cause mortality
(part of safety
assessment in
study protocol)
Day 14, day
28, EOS
Yes No
Blue font: primary endpoint
5.4.4.1 APEKs-cUTI
APEKS-cUTI was a Phase 2, multicentre (multinational), double-blind, randomised, active-
controlled, parallel-group study including 452 patients diagnosed with complicated urinary tract
infection [51] Clinicaltrials.gov Record NCT02321800).
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The Figure 29 below summarizes the trial design and displays relevant endpoints.
Cefiderocol demonstrated noninferiority to high-dose extended infusion meropenem with
regard to all-cause mortality at Day 14. The all-cause mortality rate was 12.4% (18/145
subjects) for the cefiderocol group and 11.6% (17/146 subjects) for the HDhigh-doseHD
meropenem group, demonstrating the noninferiority of cefiderocol, as the upper limit of the
95% CI was < 12.5% (95% CI: −6.6, 8.2) (Figure 41).
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Figure 41: All-cause Mortality (mITT)
[a] Treatment difference (cefiderocol minus
meropenem) is the adjusted estimate of the
difference in the all-cause mortality rate at Day
14 and Day 28 between the 2 treatment arms
based on Cochran-Mantel Haenszel weights
using APACHE II score (≤ 15 and ≥ 16) as the
stratification factor.; [b] The 95% CI (2-sided)
is based on a stratified analysis using
Cochran-Mantel Haenszel weights using
APACHE II score (≤ 15 and ≥ 16) as the
stratification factor. The CI was calculated
using a normal approximation to the difference
between 2 binomial proportions (Wald method). Source: Data on file [239]
Table 60: Day 14 All-cause Mortality (mITT and ME-PP Populations)
Population Cefiderocol n/N’ (%)
HD Meropenem n/N’ (%)
Total n/N’ (%)
Treatment Differencea
Difference (%) 95% CIb p-value
mITT N = 145 18/145 (12.4)
N = 147 17/146 (11.6)
N = 292 35/291 (12.0)
0.8 (−6.6, 8.2) 0.0020c
0.8321d
ME-PP N = 105 13/105 (12.4)
N = 101 13/100 (13.0)
N = 206 26/205 (12.7)
−0.3 (−9.4, 8.7) nc
mITT excl meropenem resistante
N = 145 9/91 (9.9)
N = 147 10/90 (11.1)
N = 292 19/181 (10.5)
−1.3 (−10.1, 7.5)
nc
APACHE II = Acute Physiology and Chronic Health Evaluation II; CI = confidence interval; CLSI = Clinical and Laboratory Standards Institute; Day 14 ACM = all-cause mortality at Day 14 since first infusion of study drug; excl = excluding; ME-PP = microbiologically-evaluable per-protocol; mITT = modified intent-to-treat; n = number of subjects who died; nc = not calculated; N = number of subjects in the analysis set; N’= number of subjects with known survival status [a] Treatment difference (cefiderocol minus meropenem) is the adjusted estimate of the difference in the all-cause mortality
rate at Day 14 and Day 28 between the 2 treatment arms based on Cochran-Mantel Haenszel weights using APACHE II score (≤ 15 and ≥ 16) as the stratification factor.
[b] The 95% CI (2-sided) is based on a stratified analysis using Cochran-Mantel Haenszel weights using APACHE II score (≤ 15 and ≥ 16) as the stratification factor. The CI was calculated using a normal approximation to the difference between 2 binomial proportions (Wald method).
[c] p-value for non-inferiority hypothesis. [d] p-value for the superiority hypothesis. [e] Meropenem-resistant subjects were those subjects whose baseline Gram-negative pathogens were resistant to
meropenem based on CLSI susceptibility results. Subjects who did not have any susceptibility results available at baseline based on CLSI were not included for this analysis.
Source: Tables 14.2.1.1.1, 14.2.1.1.3, and 14.2.1.1.4
The sensitivity analysis of Day 14 all-cause mortality using the ME-PP population is in support
of the noninferiority finding in the primary efficacy population (Table 60). In a supplementary
analysis of the primary endpoint, in which subjects who were resistant to HD meropenem were
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excluded from the mITT population, Day 14 all-cause mortality was 9.9% in the cefiderocol
group and 11.1% in the HD meropenem group (Table 60).
Subgroup analyses revealed no statistically significant differences between the included
groups (Figure 42).
Figure 42: Primary efficacy results: Day 14 All-cause Mortality by Subgroups
Source: Data on file [239]
5.4.4.3.2 Secondary efficacy endpoints
Rates of microbiological eradication and clinical cure at TOC confirmed the non-inferiority
between the treatments (Table 61). 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.
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Table 61: Secondary Endpoints (mITT Population)
Endpoint
Cefiderocol (N = 145) n/N’ (%)
HD Meropenem (N = 147) n/N’ (%)
Total (N = 292) n/N’ (%)
Treatment Comparison
Difference (%) 95% CI
Microbiological eradication at TOC
59/124 (47.6) 61/127 (48.0)
120/251 (47.8) -1.4 a (-13.5, 10.7) a
Clinical cure at TOC
94/145 (64.8) 98/147 (66.7)
192/292 (65.8) -2.0 a (-12.5, 8.5) a
Day 28 all-cause mortality
30/143 (21.0) 30/146 (20.5)
60/289 (20.8) 0.5b (-8.7, 9.8)b
EOS all-cause mortality
38/142 (26.8) 34/146 (23.3)
72/288 (25.0) 3.6b (-6.3, 13.4)b
APACHE II = Acute Physiology and Chronic Health Evaluation II; CI = confidence interval; EOS = end of study; mITT = modified intent=to-treat; TOC = test of cure [a] Treatment difference (cefiderocol minus meropenem) is the adjusted estimate of the difference in the eradication
rate or cure rate between the 2 treatment arms. The adjusted difference estimates and the 95% CIs (2-sided) were calculated using a stratified analysis with Cochran-Mantel-Haenszel weights based on the stratified factors at baseline, infection type (HABP/VABP/HCABP), and APACHE II score (≤ 15 and ≥ 16).
[b] Treatment difference (cefiderocol minus meropenem) is the adjusted estimate of the difference in the all-cause mortality rate at Day 28 or at the EOS visit between the 2 treatment arms based on Cochran-Mantel Haenszel weights using APACHE II score (≤ 15 and ≥ 16) as the stratification factor. The 95% CI (2-sided) is based on a stratified analysis using Cochran-Mantel Haenszel weights using APACHE II score (≤ 15 and ≥ 16) as the stratification factor. The CI is calculated using a normal approximation to the difference between 2 binomial proportions (Wald method).
Source: Tables 14.2.2.1.1, 14.2.3.1.1, 14.2.1.1.1, and 14.2.4.1.1
Cefiderocol has demonstrated similar all-cause mortality at Day 28, clinical and microbiological
outcomes to HD meropenem (Table 62) [239]. 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 [239]. All-cause mortality at Day 28 and at EOS was also similar
between the treatment groups [239].
Table 62: Secondary Endpoints (mITT Population)
Endpoint
Cefiderocol
(N = 145) n/N’ (%)
HD meropenem
(N = 147)
n/N’ (%)
Microbiological eradication at TOC 59/124 (47.6) 61/127 (48.0)
Clinical cure at TOC 94/145 (64.8) 98/147 (66.7)
Day 28 all-cause mortality 30/143 (21.0) 30/146 (20.5)
EOS all-cause mortality 38/142 (26.8) 34/146 (23.3)
EOS, end of study; TOC, test of cure
Source: Data on file [239]
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Efficacy data across different pathogens
A similar response between cefiderocol and HD meropenem was observed across different
pathogens (Table 63) [239].
Table 63: Clinical and microbiological outcome per baseline pathogen
Cefiderocol (n=145)
HD Meropenem (n=147)
Treatment comparison
Difference (%)
95% CI
Clinical cure at TOC (mITT)
K. pneumoniae 31/48 (64.6) 29/44 (65.9) −1.3 (−20.8, 18.1)
P. aeruginosa 16/24 (66.7) 17/24 (70.8) −4.2 (−30.4, 22.0)
A. baumannii 12/23 (52.2) 14/24 (58.3) −6.2 (−34.5, 22.2)
E. coli 12/19 (63.2) 13/22 (59.1) 4.1 (−25.8, 33.9)
Microbiological eradication at TOC (mITT)
K. pneumoniae 22/48 (45.8) 24/44 (54.5) −8.7 (−29.1, 11.7)
P. aeruginosa 9/24 (37.5) 11/24 (45.8) −8.3 (−36.1, 19.5)
A. baumannii 9/23 (39.1) 8/24 (33.3) 5.8 (−21.7, 33.2)
E. coli 10/19 (52.6) 11/22 (50.0) 2.6 (−28.0, 33.3) HD, high-dose; TOC, test of cure; Source: Data on file [239]
5.4.4.3.3 Efficacy data based on susceptibility to meropenem
In a subgroup analysis including a small sample of patients with meropenem-non-susceptible
Gram-negative pathogens (as per CLSI break point of 8mg/L), post hoc analyses of subjects
with values of > 16 μg/mL, > 32 μg/mL, and > 64 μg/mL, showed a trend of lower mortality in
the cefiderocol group than in the meropenem group at Day 14 and Day 28; however, the
sample sizes are too small to draw definitive conclusions (Figure 43) [239].
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Figure 43: Day 14 and Day 28 all-cause mortality according to MIC for meropenem
HD, high dose; MIC, minimum inhibitory concentration; Source: Data on file [239]
Microbiological and clinical outcomes at TOC in the subgroup of meropenem-nonsusceptible
subjects are shown in Table 64. The meropenem–nonsusceptible subgroup includes
intermediate and resistant categories of susceptibility. At TOC, the microbiological eradication
rate was 40.0% (14/35) in the cefiderocol group and 33.3% (10/30) in the meropenem group,
and the clinical cure rate was 57.1% (20/35) in the cefiderocol group and 56.7% (17/30) in the
meropenem group.
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Table 64: Microbiological and Clinical Outcome for the Meropenem-non-
CI = confidence interval; CLSI = Clinical and Laboratory Standards Institute; EOS = end of study; mITT = modified intent=to-treat; N’ = number of meropenem-nonsusceptible subjects; TOC = test of cure [a] The meropenem-nonsusceptible status for subjects was Yes if for any baseline Gram-negative pathogens
(including Stenotrophomonas maltophilia) the CLSI results were nonsusceptible to meropenem. Subjects who did not have any susceptibility results available at baseline based on CLSI were not included for this analysis.
[b] Treatment difference is cefiderocol minus meropenem. The 95% CIs (2-sided) of treatment difference were calculated using a normal approximation to the difference between the 2 binomial proportions (Wald method). The CIs for cure rates within a visit with less than 10 subjects in any treatment arm are not presented.
Source: Tables 14.2.2.1.4 and 14.2.3.1.4
When analyzing microbiological eradication rates based on different CLSI MIC for
meropenem in the non-susceptible group, data suggests that cefiderocol retains
microbiological eradication as MIC for meropenem increases, whereas for it HD
meropenem decreased (Figure 44).
Figure 44: Microbiological eradication by MIC at EOT
EOT, end of treatment; HD, high dose; MIC, minimum inhibitory concentration; Source: Data on file [239]
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Feasibility for NMA in nosocomial pneumonia:
A feasibility assessment was carried out for an NMA for APEKS-NP trial. It proved
not to be possible to conduct an NMA, given that the comparator used in APEKS
NP trial (HD meropenem) was not used in other trials alone, and there was no
bridging study. Even though the molecule is the same, this higher dose and
prolonged infusion optimizes efficacy of meropenem. In addition, APEKS NP
included difficult to treat pathogens such as Acinetobacter baumannii, which are
not included in other clinical trials because they are not susceptible to the newer
drugs. For full information on the feasibility assessment please refer to [227].
5.4.4.4 Comparative analysis of estimated success rates considering the European pathogen epidemiology in the population with suspected MDR/CR infections
In the absence of antibiogram, cefiderocol provides the best predicted susceptibility rates and
estimated success rates considering the European pathogen epidemiology
When critically ill patients require immediate treatment in the absence of AST, the likelihood of
treatment success with cefiderocol and comparators can be predicted through a simple
effectiveness model, that projects the clinical trials outcomes in terms of microbiological
eradication and clinical cure for each of antimicrobials, for a scenario where an antimicrobial
prescription is required in the absence of an antibiogram for a suspected MDR pathogen. This
analysis is therefore based on epidemiology (pathogen prevalence estimates for the specific
site of infection, taken from eCDC) and pathogen susceptibility results (taken from the SIDERO
studies, when selecting pathogens already resistant to ciprofloxacin and cefepime), relying on
drug’s ability to achieve effective concentrations to the infections site. This weighed
susceptibility is then overlaid with the individual relevant antimicrobial outcomes in the clinical
trials for each infection site.
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Results for cUTI and pneumonia are shown below [266-269].
Table 65: Susceptibility and effectiveness model predicting outcomes for
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BAT = best available therapy; INC = increase from baseline; PT-INR = prothrombin time-international normalized ratio;
ULN = upper limit of normal; Percentage is calculated using N’ as the denominator, where N’ is the number of subjects with valid postbaseline measurements.
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5.5.2 Safety analyses by clinical trial
5.5.2.1 APEKS cUTI
Cefiderocol was generally safe and well-tolerated in the cUTI study, with a safety profile
consistent with other cephalosporin antibacterials. Adverse events (AEs) and serious adverse
events (SAEs) were comparable between the cefiderocol and imipenem groups. The safety
profile of cefiderocol supports its use in cUTI.
5.5.2.1.1 Extent of Exposure
Safety Analysis Population
Of 452 subjects randomized, 448 received at least 1 dose of the study drugs and were included
in the Safety Population (99.0% [300/303] of subjects in the cefiderocol group and 99.3%
[148/149] of subjects in the IPM/CS group) (Table 82). Of the subjects in the Safety Population,
93.4% (283/303) of randomized subjects in the cefiderocol group and 92.6% (138/149) of
randomized subjects in the IPM/CS group completed the study.
Subjects were excluded from the Safety Population for no study drug infusion (1.0% [3/303]
of subjects in the cefiderocol group and 0.7% [1/149] of subjects in the IPM/CS group). Study
blind was broken for 4 subjects. All four were unblinded before the database was locked to
Discontinuation due to TEAEs 12 (8.1) 18 14 (9.3) 19 -1.2 (-7.6, 5.2)
Discontinuation due to
treatment-related TEAEs
2 (1.4) 4 2 (1.3) 3 0.0 (-2.6, 2.6)
CI = confidence interval; TEAEs = treatment emergent adverse events; SAEs = serious adverse events; Percentage was calculated using the number of subjects in the column heading as the denominator. Adverse events that started on or after the first dose date of the study drug and up to ‘End of Study’ were defined as treatment-emergent. Confidence intervals were calculated using the Wilson score method. Source: APEKS-NP Study Synopsis[238]
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Adverse events with the highest frequency in the cefiderocol group (urinary tract infection
[15.5%], hypokalemia [10.8%], diarrhea [8.8%], and anemia [8.1%]) were also the most
frequent AEs in the high-dose meropenem group (hypokalemia [15.3%], urinary tract infection
[10.7%], diarrhea [8.7%], and anemia [8.0%]) [262, 263].
5.5.2.3.2 Overview of TEAEs
Most subjects in the cefiderocol group and meropenem group experienced at least 1 TEAE
(87.8% [130/148] and 86.0% [129/150], respectively) (Table 88). SAEs were reported in 36.5%
(54/148) in the cefiderocol group and 30.0% (45/150) in the meropenem group. Overall,
treatment-related TEAEs and SAEs, TEAEs leading to death and discontinuation were
reported with similar frequency in the two treatment groups.
5.5.2.3.3 Common TEAEs
The most commonly reported TEAEs (i.e. TEAEs reported in ≥5% of subjects in either
treatment group) are summarised by PT in Table 119-9. All TEAEs are reported by SOC and
PT in a safety data on file[262, 263]. The most commonly reported TEAEs were from the
following SOCs:
Infections and Infestations: in 40.5% (60/148) and 35.3% (53/150) of subjects in
the cefiderocol and meropenem groups, respectively
Metabolism and nutrition disorders: in 29.1% (43/148) and 31.3% (47/150) of
subjects in the cefiderocol and meropenem groups, respectively.
Specifically, the most common TEAEs were urinary tract infection in the cefiderocol group (in
15.5% [23/148] of subjects compared with 10.7% [16/150] in the meropenem group) and
hypokalaemia in the meropenem group (in 15.3% [23/150] of subjects compared with 10.8%
[16/148] in the cefiderocol group). Most TEAEs were reported with similar frequency in the two
treatment groups. TEAEs reported more frequently (>4% difference between treatment
groups) in the cefiderocol group than in the meropenem group were: urinary tract infection (in
15.5% [23/148] vs. 10.7% [16/150] of subjects) and hypomagnesaemia (in 5.4% [8/148] vs.
0.7% [1/150] of subjects). TEAEs reported less frequently in the cefiderocol group than in the
meropenem group (>4% difference between treatment groups) were: hypokalaemia (in 10.8%
[16/148] vs. 15.3% [23/150] of subjects), hepatic enzyme increased, hyponatraemia and
decubitus ulcer (each in 2.7% [4/148] vs. 6.7% [10/150] of subjects), and hypotension (in 1.4%
[2/148] vs. 6.7% [10/150] of subjects).
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5.5.2.3.4 TEAEs by severity
Overall, the proportions of subjects experiencing mild, moderate or severe TEAEs was 23.5%
(70/298), 29.5% (88/298) and 33.9% (101/298), respectively. The incidence of severe TEAEs
was 37.8% (56/148) in the cefiderocol group compared with 30.0% (45/150) in the high-dose
meropenem group.
5.5.2.3.5 Severe TEAEs
The most common severe TEAEs were: cardiac arrest was reported in 4.7% (7/148) in the
cefiderocol group and 3.3% (5/150) in the high-dose meropenem group, and pneumonia, was
reported in 4.7% (7/148) and 2.0% (3/150), respectively; brain oedema was reported in 0.7%
(1/148) subjects in the cefiderocol group compared with 3.3% (5/150) in the meropenem
group.Treatment-related TEAEs
Treatment-related TEAEs are presented by SOC and PT in Table 86. Overall, the incidence
of treatment-related TEAEs was 9.5% (14/148) in the cefiderocol group and 11.3% (17/150)
in the meropenem group. The most common treatment-related TEAE was diarrhoea, reported
for 2.0% (3/148) subjects in the cefiderocol group compared with 3.3% (5/150) subjects in the
meropenem group.
All treatment-related TEAEs associated with increases in liver enzyme in the cefiderocol group
were transient and resolved or were resolving during the study. Overall, the majority of
treatment-related TEAEs were either mild (n=15) or moderate (n=20), while 11 were severe.
5.5.2.3.6 Deaths
The primary objective of this study was to compare all-cause mortality between the 2 groups
at Day 14 after start of study drug therapy in the mITT population. All-cause mortality rates for
the mITT population are reported in the efficacy section.
5.5.2.3.7 Other SAEs
All SAEs reported during the study are presented by SOC and PT on file [238]. Overall, the
frequency of SAEs was 36.5% (54/148) in the cefiderocol group compared with 30.0%
(45/150) in the meropenem group. Overall, the most common SAE was cardiac arrest,
reported in 4.7% (7/148) in the cefiderocol group compared with 3.3% (5/150) in the
meropenem group.
Overall, treatment-related SAEs were reported in 2.0% (3/148) in the cefiderocol group
compared with 3.3% (5/150) in the meropenem group [238].
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Table 89 – Number (percent) of subjects with serious adverse events (SAEs) by organ class and preferred term (safety population)
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5.5.2.3.8 TEAEs leading to study treatment discontinuation
All TEAEs leading to study treatment discontinuation are presented by SOC and PT in Table
119-13. TEAEs leading to study treatment discontinuation were reported for 8.1% (12/148) in
the cefiderocol group and 9.3% (14/150) in the meropenem group. Alanine aminotransferase
increased was the most frequently reported TEAE leading to discontinuation, in 2/148 (1.4%)
subjects in the cefiderocol group. Hepatic enzymes increased was reported in no subjects in
the cefiderocol group and 5/150 (3.3%) in the HD meropenem group. All other TEAEs leading
to discontinuation were reported at most in 1 subject in either treatment group.
5.5.2.3.9 Conclusions for APEKS-NP Study
Overall, the types and frequency of TEAEs for cefiderocol were generally similar to high-dose
meropenem and consistent with safety profile of cephalosporin class of antibacterials.
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5.5.2.4 CREDIBLE-CR
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
5.5.2.4.1 Treatment-Emergent Adverse Events
Over 90% of the subjects in each treatment group had at least 1 adverse event (Table 90).
The incidence of treatment-related adverse events was 14.9% in the cefiderocol group and
22.4% in the BAT group. The incidence of adverse events with an outcome of death by the
end of the study was 33.7% in the cefiderocol group and 18.4% in the BAT group. Of note,
none of the deaths in the cefiderocol group were considered related to study treatment by
either the investigator or Shionogi. The percentage of reported serious adverse events was
49.5% in the cefiderocol group and 46.9% in the BAT group. Overall, 6 subjects experienced
treatment-related serious adverse events (1 in the cefiderocol group and 5 in the BAT group).
The percentage of discontinuations due to adverse events was 9.9% in the cefiderocol group
and 6.1% in the BAT group.
Table 90: Overview of Treatment-emergent Adverse Events (Safety Population)
that are worsening from baseline or occur thereafter in
the course of the study, the investigator or sub-
investigator will consider whether these results are
clinically significant. Abnormal laboratory test results are
defined as values outside the reference range. Any test
results which are clinically significant at the discretion of
the investigator or sub investigator are to be recorded
as AEs. If an abnormal laboratory finding is associated
with disease or organ toxicity, the investigator should
report only the disease or organ toxicity as AEs. These
AEs should also be assessed as to whether they meet
the definition of seriousness and reported accordingly.
The investigator or sub-investigator will consider test
results to be clinically significant in the following
circumstances:
Test result leads to any of the outcomes
included in the definition of an SAE.
Test result leads to discontinuation from the
study.
Test result leads to a concomitant drug
treatment or other therapy.
Test result requiring additional diagnostic
testing or other medical intervention.
Test result meeting the management criteria
for liver function abnormalities identified in the
Appendix 6 of the statistical analysis plan
(SAP).
Liver Abnormalities
Management and Discontinuation Criteria for Abnormal
Liver Function tests have been designed to ensure
subject safety and evaluate liver event aetiology. The
investigator or sub-investigator must review study
subject laboratory results as they become available to
identify if any values meet the criteria in Appendix 6.
When any test result meets the management criteria for
liver function abnormalities, the results of further
assessments and required FUP.
Serious Adverse Events (SAE)
An SAE is defined by regulation
as any AE occurring at any dose
The severity of a SAE was graded to the listed criteria.
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that results in any of the following
outcomes:
Death
Life-threatening
condition
Hospitalization or
prolongation of existing
hospitalization for
treatment
Persistent or significant
disability/incapacity
Congenital
anomaly/birth defect
Other medically
important condition
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5.6 Conclusions
1. Provide a general interpretation of the evidence base considering the benefits
associated with the technology relative to those of the comparators.
Cefiderocol is an innovative siderophore cephalosporin antibacterial with a unique molecular
structure designed to provide high stability to carbapenemases and use bacteria’s own
mechanism of iron uptake. Both these attributes enable cefiderocol to overcome three main
mechanisms of beta-lactam bacterial resistance (degradation by β-lactamase enzymes, porin
channel mutations, and overexpression of efflux pumps), which is translated in a wide activity
spectrum against aerobic Gram-negative pathogens, including the MDR and WHO critically
important carbapenem resistant strains of Enterobactereacea, A. baumanii and P. aeruginosa,
as well as intrinsically CR S. maltophilia. MDR pathogens are difficult to treat, have limited
treatment options, and no existing treatment provides both comprehensive coverage and good
safety profile. Cefiderocol therefore constitutes an effective and safe treatment option for
patients with serious infections in the presence of world-wide growing resistances.
MDR infections, including those resistant to carbapenems, primarily occur in vulnerable
hospitalised patients. The treatment of MDR-GNB infections in critically ill patients presents
many challenges are associated with poorer outcomes including increased mortality,
increased length of stay and healthcare resource utilization, compared to non-resistant
pathogens. Since an effective treatment should be administered as soon as possible,
resistance to many antimicrobial classes almost invariably reduces the probability of adequate
empirical coverage, with possible unfavorable consequences in terms of increased mortality,
length of stay and healthcare reseource utilization.
In this light, readily available patient’s medical history and updated information about the local
microbiological epidemiology remain critical for defining the baseline risk of MDR-GNB
infections and firmly guiding empirical treatment choices, with the aim of avoiding both
undertreatment and overtreatment. Treatment of severe MDR-GNB infections in critically ill
patients requires a expert and complex clinical reasoning, taking into account the peculiar
characteristics of the target population, but also the need for adequate empirical coverage and
the more andmore specific enzyme-level activity of novel antimicrobials with respect to the
different resistance mechanisms of MDR-GNB.
Due to the urgent need to develop new treatments based on the underlying pathogens rather
than the infection site, the EMA label is expected to authorize cefiderocol to be used for
treatment of infections due to aerobic Gram-negative organisms in adults with limited
treatment options
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Assessment of the effectiveness of cefiderocol is based on the integration of in vitro, PK/PD
and clinical data. Large susceptibility studies have confirmed cefiderocol wider Gram-negative
spectrum, and being a more potent antimicrobial agent than comparators. It’s very favourable
minimum inhibitory concentrations (MICs) have been shown to correlate well with in vivo
efficacy and randomized clinical trials in patients with cUTI, nosocomial pneumonia, and BSI
have provided confirmation of the efficacy and safety of cefiderocol in key target patient
populations. These reflect the label and are pathogen focused, not restricted to any specific
site of infection and supports the use of cefiderocol in two types of patients:
Hospitalised patients with suspected (but prior laboratory confirmation) MDR/CR
infection who are critically ill and require immediate antibacterial treatment that
provides full cover against CR pathogens and potential resistant mechanisms, to
avoid the risk of rapid clinical deterioration (with the option to de-escalate to a more
targeted treatment when the pathogen and susceptibility profile is subsequently
confirmed).
Hospitalised patients where CR infection has been confirmed and cefiderocol is
best option based on pathogen susceptibility information and/or where other
treatment choices are inappropriate (efficacy, contra-indication or
tolerability).Conclusions based on the in-vitro surveillance, PK/PD data and clinical
data
Cefiderocol is a time-dependent cephalosporin. Preclinical studies showed that cefiderocol
has linear pharmacokinetics, primarily urinary excretion, an elimination half-life of 2–3 hours,
and a protein binding of 58% in human plasma. The probability of a target attainment at ≥75%
of the dosing interval during which the free drug concentration exceeds the minimum inhibitory
concentration (ƒT/MIC) for bacterial strains with an MIC of ≤4 μg/mL was greater than 90% at
the therapeutic dose of 2 g over 3-hour infusion every 8 hours in most patients.
Only renal function markers were found to be influential covariates for the pharmacokinetics
of cefiderocol for patients with altered renal function. Dose adjustment is recommended for
patients with impaired and augmented renal function.
The potent activity of cefiderocol was confirmed in an extensive series of in vitro studies,
against clinical isolates from surveillance studies, and in animal infection models. The
SIDERO-WT study showed ccefiderocol to have activity against 99.5% of Gram-negative
isolates at a MIC of 4 mg/L, while the SIDERO-CR study, which only includes CR isolates,
showed cefiderocol to have potent in vitro activity at a MIC of 4 mg/L against 96.2% of isolates
of carbapenem-non-susceptible pathogens including all of the WHO priority pathogens and
Stenotrophomonas maltophilia. In both studies, cefiderocol was found to give wider Gram-
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negative coverage, and to be a more potent in vitro antibacterial agent than comparators. The
results confirm cefiderocol overcomes multiple mechanisms or resistance and to be stable
against the 4 known classes of β-lactamases, including serine carbapenemases, with potency
which is equal to or greater than comparators.
An improved in vitro potency in addition to a well-characterized favorable PK/PD profile are
crucial to achieve both adequate exposure to the antibacterial over the MIC for the pathogen,
and clinical cure in patients infected with drug-resistant pathogens [52]. Therefore, clinical
studies in antimicrobials, provide only supportive safety and efficacy evidence to the pivotal
in-vitro and PK/PD data. Furthermore, in the context of antibacterial resistance, the standard
clinical trial approach aiming at demonstrating superiority over existing treatments is not
feasible. Treatment options for MDR infections do not allow a superiority trial and it would be
unethical to wihthold effective treatment to pateints in such trials [52]. Hence, clinical trials
have an important role to confirm clinical efficacy, but a limited role in providing comparative
evidence outside the trial, as only pathogens that fall within the in-vitro spectrum of the tested
treatments and comparators are included in the study. This is particularly relevant for
antimicrobial treatment selection in the absence of antibiogram.
The clinical evidence to support the use of cefiderocol is based on 2 randomised, double
blinded clinical trials, and 1 descriptive open-label study. Data from an NMA, an effectiveness
model and compassionate use cases complement the body of confirmatory clinical data.
Low likelihood of in treatment development of resistance against cefiderocol was
demonstrated by the fact that only very few and moderate increases in the cefiderocol MIC
were seen over the treatment course, usually requiring more than 1 simultaneous mutation to
increase the MIC. Cefiderocol also presents low likelihood of generating cross resistance,
given that the main resistant pathway identified in in vitro studies was related with the
siderophore ion uptake.
5.6.1 Evidence to support use of cefiderocol in patients with infections by suspected MDR/CR pathogens:
SIDERO WT provides evidence to support the use of cefiderocol in the group of critically ill
patients with infections suspected to be caused by a MDR pathogen, who require immediate
treatment. These patients would benefit from the availability of an additional effective antibiotic
treatment providing full cover against carbapenem-resistant pathogens while pathogen
susceptibility is being confirmed.
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The SIDERO-WT study tested the in-vitro antibacterial activity of cefiderocol against Gram-
negative bacteria [29]. A total of 30,459 clinical isolates of Gram-negative bacilli were
systematically collected from USA, Canada, and 11 European countries between 2014 and
2017. Cefiderocol demonstrated activity against 99.5% of Gram-negative isolates at a MIC of
4 mg/L. Isolates were less susceptible to the comparators including colistin (95.5%),
ceftazidime-avibacatam (90.2%) and ceftolozane-tazobactam (84.3%).
In a retrospective analysis comparing the probability of target attainment (PTA) for cefiderocol,
ceftolozane/tazobactam and meropenem against Enterobacterales and Pseudomonas
aeruginosa in a representative patient population at risk of MDR or carbapenem resistant
infections, the cumulative fractions of response (CFRs) calculated using European MIC
distributions from the SIDERO surveillance for cefiderocol against Enterobacterales and
Pseudomonas spp. are considerably higher than seen for meropenem and ceftolozane-
tazobactam.
In patients with infections suspected to be caused by MDR/CR pathogens, clinical trials
only provide limited comparative evidence regarding the efficacy of new antibacterials. This is
because trials must include only pathogens for which the tested agents and comparators are
effective, as it would be unethical to knowingly allow patients to have ineffective treatment. In
this setting, standard NMAs also provide little information, as they never account for pathogens
not susceptible to the treatment regimens included in the network. A comparison of efficacy
against all relevant comparators can only be obtained from in-vitro surveillance studies. Hence
approaches integrating all available evidence from in vitro, PK/PD and clinical data (such as
effectiveness models), are the necessary to predict susceptibility rates and clinical
effectiveness rates.
APEKS-cUTI compared cefiderocol with imipenem/cilastatin (IPM/CS) in cUTI caused by
Gram-negative MDR pathogens in hospitalized adults. The study was designed to
demonstrate non-inferiority, with the primary efficacy endpoint being the composite of clinical
response and microbiological response at TOC. 73% of patients in the cefiderocol group
achieved the primary endpoint, vs only 55 % of patients in the IPM/CS group, with an adjusted
treatment difference of 18.6% (95 % CI: 8.2, 28.9). A further post-hoc analysis confirmed
superiority in favour of cefiderocol.
Given the similarority of patients and pathogens included in across trials, a NMA was
conducted to compare the result of APEKS cUTI with relevant comparator studies. Results
showed no statistically significant difference between the APEKS cUTI result and results from
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studies of ceftazidime/avibactam and ceftolozane/tazobactam conducted in a similar
population with a similar pathogen distribution.
The APEKS-NP study compared treatment with cefiderocol against high-dose and prolonged
infusion (HD) meropenem in patients with nosocomial pneumonia caused by MDR Gram-
negative pathogens. Cefiderocol met the primary endpoint of non-inferiority in ACM at day 14
versus HD meropenem (12.4% vs 11.6%; (95 % CI: -6.6, 8.2)). APEKS-NP used an improved
meropenem regimen (both high dose and prolonged infusion time) to optimize its exposure
and efficacy. This meant that a NMA was not possible because previously published
meropenem studies had used a lower dose of meropenem.
The results of the two randomized, double-blind APEKS trials combined provide highly reliable
and clinically relevant evidence to support the use of cefiderocol in patients with suspected
MDR pathogens with limited treatment options.
Furthermore, in an analysis incorporating European pathogen epidemiology and susceptibility
data, cefiderocol provides the best predicted susceptibility rates and estimated clinical and
microbiological success rates regardless of the infection site, in the absence of an antibiogram
for the critically ill patients with suspected MDR pathogen infection requiring immediate
treatment.
Combining these results and clinical data in an effectiveness model, show that cefiderocol has
a greater likelihood of achieving microbiological eradication and clinical cure, in the patients
with suspected MDR/CR infections than relevant comparators across for cUTI and
pneumonia. In the absence of antibiogram, cefiderocol provides an effective option for treating
critically ill, hospitalised patients where CR infection is suspected and time to effective
treatment must be as short as possible, increasing the likelihood of providing an initial
appropriate therapy and potentially avoiding worse morbidity and mortality outcomes
associated with delayed effective therapy.
5.6.2 Evidence to support use of cefiderocol in patients with infections by confirmed CR pathogens:
Data from the SIDERO-CR study indicate that cefiderocol maintains high activity in the
presence of beta-lactamases, carbapenemases, and strains with porin channel mutations or
efflux-pump overexpression. Patients with confirmed MDR/CR infections, for whom the
antibiogram indicates susceptibility for cefiderocol thus gain an additional treatment option
with equal or higher susceptibility than comparators.
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In the SIDERO-CR-2014-2016 study [30], which was a global study of 52 countries, focusing
only on CR isolates, cefiderocol demonstrated potent in vitro activity at a MIC of 4 mg/L against
96.4% of isolates of carbapenem-nonsusceptible pathogens including all of the WHO priority
pathogens and Stenotrophomas maltophilia. Cefiderocol was found to provide a wider Gram-
negative coverage, and more potent in vitro antimicrobial activity than comparators including
ceftazidime/avibactam (39.8%), ceftolozane/tazobactam (37%), and colistin (91.5%).
Clinical trials can provide more reliable information regarding comparative efficacy when the
pathogens have confirmed or expected susceptibility to both drugs. This is consistent with
prescription based on AST results, which occurs in patients with confirmed CR infections. In
this setting, Network meta-analysis (NMA) if feasible provide additional reliable information of
comparative effectiveness.
Evidence of clinical efficacy of cefiderocol in patients with a confirmed CR infection comes
from three sources; the APEKS NP study, the CREDIBLE CR study and the cefiderocol
compassionate use programme:
In a small subgroup of patients participating in the APEKS-NP that was non-susceptible to
meropenem considering a breakpoint of 8mg/L (MIC), similar results in terms of mortality,
clinical and microbiological outcomes were achieved between arms. However, when looking
into the stratification for pathogens with MIC >16 mg/mL, patients on cefiderocol had reduced
mortality and higher clinical cure rates. The HD prolonged infusion meropenem regimen in this
trial, increased exposure in terms of time and concentration to the infection site, increasing
the likelihood of effectiveness, even on pathogens with MIC up to 16mg/mL.
The CREDIBLE CR study was a small, randomised, open label, descriptive, exploratory, study
conducted to evaluate efficacy in patients with confirmed CR infections given cefiderocol or
BAT. The study was not designed or powered for statistical comparison between arms. The
study included 150 severely ill patients, consistent with compassionate use cases, with a
range of infection sites including nosocomial pneumonia, cUTI, BSI/sepsis. Many patients had
end stage comorbidities and had failed multiple lines of therapy. Cefiderocol and BAT were
shown to be effective in terms of clinical and microbiological outcomes in these patients,
particularly for cefiderocol also showing clinical and microbiological efficacy regardless of
carbapenemases present in the pathogen causing the infection. However, there were marked
clinically relevant differences in some baseline characteristics and pathogen distribution of the
cefiderocol and BAT arms. An imbalance in mortality was observed in the cefiderocol arm
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compared to BAT (18/49 vs 5/25), which was not considered to be related with safety signals.
No deaths were found to be causally associated with cefiderocol through assessment by the
investigator and two independent committees. No single factor that would explain the
imbalance was identified. Small patient numbers and multiple confounders preclude definitive
conclusions. Additional analyses revealed that mortality in the treatment arm was similar to
other studies in the context, while the BAT arm performed better than all reported studies,
particularly for non-fermenters. The reasons for this are not understood.
Compassionate use program: More than 200 patients were treated with cefiderocol within the
compassionate use programme around the world, demonstrating the unmet medical need.
Confirmed information on 74 patients who have completed treatment in the compassionate
use program showed that over 60% of the severely ill patients infected with CR Gram-negative
pathogens survived when no other treatment option was available to them.
The overall mortality across the compassionate use programs and CREDIBLE CR was similar,
36.5% and 33.7% respectively, supporting the notion that the population recruited into the
CREDIBLE-CR trial, included severely ill patients with a very poor prognosis, similar to those
applying for compassionate use and other similar studies reported on literature.
5.6.3 Quality of Life
Patients with these severe nosocomial infections are frequently treated in ICU units, often
unconscious, and on many occasions require ventilation (intubation), preventing investigation
of patient-reported outcomes. Because the most severely ill patients cannot complete
questionnaires, this can lead to systematic under-reporting QoL data of the most severe
courses of illness. The fact that these patients are hospitalised already has decrimental impact
on their quality of life. The ward in the hospital also impacts the patient’s quality of life (i.e
patients on ICU or isolation, are expected to have lower quality of life compared to general
ward), although this may be correlated with the severity of the infection and underlying
condition. All these factors make investigating quality of life in antimicrobial clinical trials
difficult and infrequent. The microbiological outcomes and mortality have thus been deemed
to be most relevant, also by regulators. No PROs are, therefore, reported in the dossier.
However, any therapy that resolves the infection and/or reduces length of hospitalization is
expected to improve patient’s quality of life.
5.6.4 Comparators
The in vitro data and combination of the in vitro, PK/PD, and clinical data show that cefiderocol
outperforms all relevant comparators with regard to the likelihood of obtaining microbiological
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eradication in the population with suspected MDR/CR infections. While clinical evidence is
restricted to a limited number of comparators that were deemed to be relevant in the specific
context by regulators, an NMA in the cUTI indication and the additional in vitro data reveal
favourable outcomes of cefiderocol compared with all relevant available treatments (Table
95).
Table 95 - Comparator overview
Population Comparator Data source Result (cefiderocol vs. comparator)
Suspected MDR/CR
High dose Meropenem SIDERO WT surveillance
Broader coverage of Gram-negative, aerobic pathogens. Lower MIC value and preserved efficacy in the presence of carbapenemases.
APEKS-NP RCT
Non-inferior with regard to mortality (primary outcome) and all clinical and microbiological secondary outcomes.
High dose Meropenem Ceftalozane-tazobactam, Ceftazidime-avibactam
Integrated epidemiology and in-vitro data analysis
Cefiderocol presents higher weighed susceptibility rates in cUTI, pneumonia, BSI, and gastrointestinal samples vs comparators
High dose Meropenem Ceftalozane-tazobactam, Ceftazidime-avibactam
Effectiveness model integrating epidemiology, in-vitro data and clinical data
Cefiderocol presents higher likelihood of clinical and microbiological effectiveness in pneumonia and cUTI vs comparators.
Imipenem/Cilastatin APEKS-cUTI RCT
Non-inferior to comparator, but proven superiority in a post-hoc analysis, on the primary endpoint of combined microbiological eradication / clinical cure at TOC, and secondary endpoint microbiological eradication at TOC.
In similar patient populations with similar pathogen distribution across different trials, and consistent with APEKS-cUTI there was statistical significant difference in microbiological eradication at TOC vs Imipenem/cilastatin, but in all other endpoints there was no statistically significant difference, including clinical cure rates and adverse events
Ceftolozane/tazobactam SIDERO WT surveillance
Lower MIC90 (0.25 vs. 8 for Pseudomonas, 0.25 vs. 32 for
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Acinetobacter, 1 vs. 64 for Enterobacteriaceae)6 Higher % isolates susceptible to cefiderocol
Ceftazidime/avibactam SIDERO WT surveillance
Same MIC90 for Enterobacteriaceae (1 vs. 1), otherwise superiority of cefiderocol Higher % isolates susceptible to cefiderocol
Confirmed CR
Colistin-based (combination) regimens (most relevant for for A. Baumanii, S. maltophilia, pathogens with metallobeta-lactamases)
SIDERO CR surveillance
Higher % isolates susceptible to cefiderocol; Similar in-vitro efficacy. Colistin is known to have severe side effects, especially kidney toxicity. Resistances against colistin have been reported to increase in epidemiological studies.
Ceftolozane/tazobactam (most relevant for P. aeruginosa, except pathogens with metallobeta-lactamases)
SIDERO CR surveillance
Higher percent susceptibility for cefiderocol against Acinetobacter and Pseudomonas across all included countries (MEM-NS pathogens)7
Ceftazidime/avibactam (most relevant for Enterobacterales, except pathogens with metallobeta-lactamases)
SIDERO CR surveillance
Higher percent susceptibility for cefiderocol against Acinetobacter and Pseudomonas across all included countries (MEM-NS pathogens)
Best available therapy (BAT), predominantly (combination) regimens (most relevant for A. Baumanii, S. maltophilia, pathogens with metallobeta-lactamases)
CREDIBLE-CR Descriptive results only. Evidence of eradication of resistant pathogens. Numerical, non-significant disadvantage with regard to mortality for cefiderocol compared to BAT.
2. Provide a general interpretation of the evidence base considering the harms
associated with the technology relative to those of the comparators.
The presented data demonstrate that cefiderocol has a similar safety profile compared to other
cephalosporins.
Pre-clinical studies showed that single and multiple doses of cefiderocol tested were well
tolerated in both healthy subjects and those with renal impairment. Furthermore, neither QT
interval prolongation nor drug–drug interaction via organic anion transporters was
demonstrated in healthy subjects.
The clinical safety for cefiderocol was established in the three randomised clinical trials,
including 549 treated patients, and showed a similar profile compared to other cephalosporins.
6 Longshaw et al., 2019 ID Week 7 Sato et al. 2019 ID Week
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Pooled adverse event analyses showed that there were overall less treatment emergent
adverse events with cefiderocol (344/549 [67.1%]) vs comparators (252/347 [72.6%]), as well
as less treatment related AEs, (56/549 [10.2%]) with cefiderocol vs compartors (45/347
[13.0%]).
The large APEKS trials with active comparators showed that TEAEs and treatment-related
TAEs were overall balanced between arms. In APEKS-NP, adverse events were experienced
by most subjects in both treatment groups with SAE rates being slightly higher in the
cefiderocol group (36.5%) than in in the meropenem group (30%). In the APEKS-cUTI trial,
serious adverse events (SAE) occurred less in cefiderocol-treated patients than in IPM/CS-
treated patients (5% vs 8%).
In the confirmed carbapenem-resistant CREDIBLE-CR trial, the cefiderocol group had lower
incidence of AEs and treatment-related AEs, but imbalance in mortality, SAEs and
discontinuation due to AEs, compared with BAT was observed. The incidence of treatment-
related AEs leading to discontinuation was similar between treatment groups. A blinded
adjudication committee concluded that none of the deaths was due to a drug-related AE.
The SPC details all potential risks associated with drug interactions or potential harms with
drug use in special categories of patients.
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5.7 Strengths and limitations
1. Summarise the internal validity of the evidence base, considering the study quality, the
validity of the endpoints used as well as the overall level of evidence. Include a
statement about the consistency of the results in the evidence base.
5.7.1 Risk of bias assessment
Unlike therapeutic areas, in vitro studies are key sources of data to substantiate clinical use
of the antibacterials. Traditionally this falls outside the scope of bias assessment, as
theoretically the risk of bias is considered minimal. In this case, same isolates were tested for
all comparators, the methodology used was based on standard defined methods, and data
was reported. The manufacturer provided the study protocol, and several publications for this
assessment; thus, the possibility of selective outcome reporting is regarded as low.
In summary, robustness of the study is ensured through large number of isolate samples,
testing same sample for all comparators. The study shows high internal validity with low risk
of bias.
In addition to the in vitro and PK/PD data, the evidence base in the population with suspected
MDR/difficult-to-treat infections is amended by two RCTs, the APEKS cUTI and APEKS NP
trials. Both studies were multicentre, multinational, double-blind, randomized, active-controlled
studies.
APEKS-cUTI was a Multicentre, Double-blind, Randomized, Clinical Study to Assess the
Efficacy and Safety of Intravenous S-649266 (Cefiderocol) in Complicated Urinary Tract
Infections with or without Pyelonephritis or Acute Uncomplicated Pyelonephritis Caused by
Gram-Negative Pathogens in Hospitalized Adults in Comparison with Intravenous
Imipenem/Cilastatin. Randomization was stratified according to the patient’s clinical diagnosis,
(cUTI with or without pyelonephritis and AUP) and region (North America, European Union,
Russia, and Japan plus the rest of world). Randomization used a computer-generated
randomization list (IXRS® provider), an interactive web or voice response system
(IWRS/IVRS) was used to assign a total of 450 patients to identification numbers for which
treatment has already been randomly assigned. Patients and investigator, site personnel, the
sponsor, and the sponsor’s designees involved in blinded monitoring, data management, or
other aspects of the study were blinded to treatment assignment. The site pharmacist or
qualified designee who prepared the intravenous infusion solution was the only study site
personnel with the identification of the study drug assignments for that site. Generation of
randomization sequence and allocation concealment are considered adequate for this
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study. Performance and detection bias were minimized through the described blinding and
alignment of infusion duration. mITT population proportions were comparable in both arms
with 252/300 for cefiderocol and 119/148 for IPM/CS thus reducing the likelihood of attrition
bias. The main study publication (Portsmouth et al 2018) reported primary outcome
(composite outcome at TOC) by predefined subgroups and microbiological and clinical
secondary outcomes at the predefined time points EA, EOT, TOC, FU as well as any AE,
treatment-related AEs, SAEs, AEs leading to discontinuation, deaths and AEs in at least 2%
of patients in either treatment group. The manufacturer provided the study protocol, SAP, CSR
and study synopsis for this assessment; thus, the possibility of selective outcome reporting
is regarded as low.
In summary, robustness of the study is ensured through randomization and stratification,
blinding and large number of patients. The study shows high internal validity with low risk of
bias at the study level.
APEKS-NP was a Phase 3, Multicentre, Randomized, Double-blind, Parallel-group, Clinical
Study of Cefiderocol Compared with Meropenem for the Treatment of Hospital-acquired
Bacterial Pneumonia, Ventilator-associated Bacterial Pneumonia, or Healthcare-associated
Bacterial Pneumonia Caused by Gram-negative Pathogens. Treatments were randomized to
subject identification numbers by the interactive response technology (IRT) provider in a 1:1
fashion to cefiderocol or meropenem. An IRT was used to assign a total of 300 subjects to
identification numbers for which treatment has already been randomly assigned.
Randomization was performed by the stratified randomization method using their infection
type (HABP, VABP, and HCABP) and APACHE II score (≤ 15 and ≥ 16) as allocation factors.
Linezolid infusion did not require blinding and was labelled with the study number, subject’s
identification number, and infusion rate and drug name. Patients and investigator, site
personnel, the sponsor, and the sponsor’s designees involved in blinded monitoring, data
management, or other aspects of the study were blinded to treatment assignment. The site
pharmacist or qualified designee who prepared the intravenous infusion solution was the only
study site personnel with the identification of the study drug assignments for that site.
Generation of randomization sequence and allocation concealment are considered
adequate for this study. Performance and detection bias were minimized through the
described blinding and alignment of infusion duration. mITT population proportions were
comparable in both arms with 145/148 for cefiderocol and 147/150 for high dose meropenem,
equally the microbiologically-evaluable Per-protocol (ME-PP) population was balanced (105
for cefiderocol and 101 for high dose meropenem), thus reducing the likelihood of attrition
bias. Results of the study have been presented in an international clinical conference, but
have not yet been published as a manuscript and no results have been posted at
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clicnitrials.gov yet, however, the manufacturer provided the study protocol, SAP, and in the
absence of available CSR at the date of EUnetHTA submission, the manufacturer also
provided study synopsis and all the documentation submitted to EMA for this assessment thus
possibility of selective outcome reporting is regarded as low.
Thus, robustness of the study is ensured through randomization and stratification, blinding
and large number of patients. The study shows high internal validity with low risk of bias at
study level.
CREDIBLE-CR was a Multicentre, Randomized, Open-label Clinical Study of S-649266 or
Best Available Therapy for the Treatment of Severe Infections Caused by Carbapenem-
resistant Gram-negative Pathogens.
The study is a small descriptive study, with no inferential analysis planned. The treatments
were randomized to subject identification numbers by the IXRS® provider in a 2:1 fashion, i.e.
to cefiderocol and BAT, respectively. An interactive web or voice response system
(IWRS/IVRS) was used to assign patients to identification numbers for which treatment has
already been randomly assigned. Randomization was performed by the stochastic
minimization method using the infection site (HAP/VAP/HCAP, cUTI, and BSI/sepsis),
APACHE II score (≤15 and ≥16), and region (N. America, S. America, Europe, and Asia-
Pacific) as allocation factors, but did not account for pathogen stratification or other clinically
relevant factors. To avoid deterministic allocation based on the ongoing allocation results,
probabilistic allocation was incorporated [Pocock SJ, Simon R. Sequential Treatment
Assignment with Balancing for Prognostic Factors in the Controlled Clinical Trial. Biometrics
1975; 31: 103-15.]. Planned proportions were approximately 50% with HAP/VAP/HCAP; cUTI
no more than 30% and the remainder of patients were enrolled under the BSI/sepsis
diagnosis. The randomization ratio of patients between treatment groups based on clinical
diagnosis was maintained through the allocation factor of clinical diagnosis at the time of
randomization. BAT was the standard of care for CR infections at each enrolling study site
and could include up to three antibiotics with Gram-negative coverage used in combination.
The comparator BAT could not be defined in the protocol and BAT was determined by the site
investigator based on the assessment of the patient’s clinical condition and had to be
determined by the investigator prior to randomization. The dosage of BAT was adjusted
according to the local country-specific label. De-escalation of BAT was allowed. Concomitant
antibiotics were allowed if the patients had a confirmed/suspected Gram-positive or anaerobic
co-infection (e.g., vancomycin, daptomycin, linezolid, clindamycin, or metronidazole).
Performance and detection bias cannot be ruled out due to the open-label design. mITT
population proportions were comparable in both arms and populations were balanced
reducing the likelihood of attrition bias. Results of the study have not been published yet and
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no results have been posted at clinitrials.gov yet but have been presented to FDA for an
Advisory Committee Meeting and made publicly available in the briefing book. Furthermore,
the manufacturer provided the study protocol, SAP, results summary and in the absence of
available CSR at the date of EUnetHTA submission, the manufacturer also provided study
synopsis and all the documentation submitted to EMA, for this assessment thus possibility of
selective outcome reporting is regarded as low.
In summary, the CREDIBLE-CR study is a small open-label, randomized, multinational,
parallel-group, Phase 3 clinical trial designed as descriptive study. Through its open-label
design, small number of patients and non-inferential design, the study shows unclear internal
validity and high risk of bias at study level.
Table 96: Risk of bias on study level – Randomized trials with cefiderocol
Study
Ad
eq
uate
ge
nera
tio
n o
f
ran
do
miz
ati
on
seq
ue
nce
Ad
eq
uate
allo
cati
on
co
nc
ealm
en
t
Blinding
Rep
ort
ing
of
ind
ivid
ua
l
ou
tco
mes i
nd
ep
en
de
nt
of
resu
lts
No
oth
er
asp
ects
of
bia
s
Ris
k o
f b
ias o
n s
tud
y
level
Pati
en
t
Tre
ati
ng
Sta
ff
<yes/no/
unclear>
<yes/no/
unclear>
<yes/no/
unclear>
<yes/no/
unclear>
<yes/no/
unclear>
<yes/no/
unclear> <high/low>
RCTs
APEKS NP yes yes yes yes yes yes low
APEKS cUTI yes yes yes yes yes yes low
Descriptive Trial
CREDIBLE CR yes no no no yes* no+ high
*Results of the study have not been published yet and no results have been posted at clicnitrials.gov yet. The manufacturer
provided the study protocol, SAP, CSR and study synopsis for this assessment thus possibility of selective outcome reporting is
regarded as low. +Several unbalances detected after study conclusion
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5.7.2 Discussion
Unlike other therapeutic areas, the evaluation of an antimicrobial relies on the combined
consideration of in vitro, PK/PD and clinical data. This is because of the primary importance
of confirming pathogen susceptibility, and theoretically, if the pathogen is susceptible to the
antimicrobial and it has adequate exposure in the infection site, the antibacterial therapy
should be effective. The main evidence supporting efficacy of cefiderocol against a wide range
of Gram-negative, aerobic pathogens thus comes from several large in-vitro surveillance
studies, which were further confirmed by independent national studies in five European
countries (Germany, Italy, Greece, Switzerland, UK). PK/PD studies showed that cefiderocol
could reach target tissues in adequate concentrations at the recommended dosing regimen.
Clinical trials served to confirm efficacy predicted based on the in vitro and PK/PD results.
In vitro testing was performed in iron-depleted broth, a standardized methodology that has
been independently validated and approved. In vitro testing results are critical for clinical
decision making, and the low MIC values reported from the studies together with the
favourable PK/PD data indicate that cefiderocol is likely to will demonstrate clinical activity
against the target Gram-negative, aerobic pathogens regardless of the infection site.
A clinical study in healthy volunteers [8] showed that the penetration ratio of cefiderocol into
ELF was comparable with that of ceftazidime in critically ill patients (0.229 based on free
plasma using a protein unbound fraction of 0.9).
The fraction of time during the dosing interval where free concentration exceeded the MIC
(fT>MIC) for a PD target was reported to be 75%. PK/PD modelling confirmed that with
probabilities of 97% in plasma and 88% in ELF free cefiderocol concentration of 4 mg/L could
be achieved using the recommended dosing regimen. Outcomes of the APEKS-NP trial, which
focused on pneumonia, lent further support to cefiderocol’s adequate penetration into lung
tissues.
In general, clinical trials can only provide very limited evidence regarding the efficacy of new
antibiotics in a real-world population of patients with suspected MDR/CR-resistant pathogens,
because trials must focus on pathogens for which the tested agents are effective; otherwise,
they would be un-ethical. Because trials thus focus on pathogens that fall within the in vitro
spectrum of the tested treatments and comparators, it is difficult to conduct network-meta-
analyses based on these trials. Since each trial excludes patients for which a poor outcome
for the candidate treatment is expected, meta-analysis will only provide answers about the
In line with ethical standards, most effective comparators (IMP/CS and HD meropenem) were
chosen for the APEKS studies. Following good stewardship practice and at request of EMA
BAT was decided to be appropriate to be administered in CREDIBLE-CR study.
Outcomes and timing: Standard outcomes for antibiotic treatment such as clinical and
microbiological outcomes as well as composite clinical and microbiological endpoints and
microbiological and clinical response per-pathogen and per-patient at different time points
(early assessment, end of treatment (EOT), test of cure (TOC), follow-up (FUP)) were
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collected in the respective trials. Clinical endpoints were in line with site of infections and
severity of disease:
For cUTI the primary efficacy endpoint was the composite of clinical response and
microbiological response at the test of cure (TOC).
For nosocomial pneumonia (HAP/VAP/CAP) the primary outcome was all-cause
mortality at day 14.
For HAP/VAP/CAP and bloodstream infections/sepsis in CREDIBLE CR study primary
endpoint was clinical cure at TOC, for cUTI it was microbiological outcomes at TOC.
All of these endpoints are main outcomes routinely assessed for antimicrobial studies
according to current regulatory standards. All endpoints considered in the trials adequately
measure relevant outcomes and follow established practice. Quality of life could not be
assessed for the stated reasons.
A full clinical assessment of cefiderocol’s value needs to consider several important pieces of
contextual information:
Delays in appropriate antibiotic therapy lead to worse clinical outcomes. This means
that an additional treatment that can target pathogens with a high unmet need can lead
to more effective early treatment and improved clinical outcomes.
Resistance rates are increasing. A dramatic slump in the development of new antibiotic
treatments in the past two decades lead to lack of treatment options for current and
future resistances.
o New treatments that show non-inferiority with all available treatments can turn
out to become life-saving last-resort options in the future, when more and more
pathogens have become resistant to the existing options.
o In addition to the static assessment of the current treatment landscape, a
dynamic assessment that includes future trends is necessary to fully
understand the current and future benefit of new antibiotic treatments.
Overall, the evidence provided in this dossier supports the clinical benefit of cefiderocol as an
additional treatment option for patients with Gram-negative, aerobic infections with limited
treatment options. As is true for all antibiotics, clinical use of cefiderocol will be based on the
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integration of in vitro susceptibility data, hospital-wide antibiograms, monitoring resistance
trends, and individual patient needs.
Within the expected pathogen based indication, it is proposed that cefiderocol offers most
value in two clinical scenarios:
Hospitalised patients with suspected MDR/CR infection who are at risk of rapid
deterioration and require antibiotic treatment that provides full cover against
carbapenem-resistant pathogens in the period while pathogen susceptibility is being
confirmed.
Hospitalised patients with a confirmed MDR/CR infection where existing treatment
options are inappropriate because of pathogen susceptibility, contraindications or poor
tolerability
Given the growing threat from MDR/CR infection and the limitations of currently available
treatment options both populations have a high unmet medical need. Advances in fast
diagnostics will allow clinicians to make decisions about effective treatment options earlier and
earlier. The recent advent of several new treatment options, together with such early
diagnostics holds promise to improve outcomes for critically ill patients and slow down the
further spread of resistant pathogens. Economic evaluations of antibiotics based on these
clinical data will need to take the full spectrum of benefits into account (e.g., enablement of
chemotherapy, high-risk surgeries).
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APPENDICES AND ATTACHMENTS
Please see separate file attached with submission dossier