Fetroja® (Cefiderocol)

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Available susceptibility testing methods for Fetroja A closer look into Fetroja for microbiologists Fetroja overcomes the 3 major, often coexisting, Gram-negative Fetroja® (cefiderocol) HardyDisk™ resistance mechanisms1,10,11,22-24 The world’s only siderophore cephalosporin—uses iron 1 Fetroja remains active in the presence of all these mechanisms, which often coexist in to gain bacterial cell entry, along with passive porin entry hard-to-treat pathogens such as A baumannii complex and P aeruginosa1, 11, 22-25 Cefiderocol 30 µg disk: Fetroja remains active against all of these mechanisms To survive in the host environment, bacteria use siderophores to actively uptake iron2,3 • Visit www.hardydiagnostics.com or call 1-800-266-2222 to order • Catalog numbers: single pack, Z9431; 5-pack, Z9435 Fetroja Bacteria 1 Bacterial growth 3 Bacteria respond to low iron concentration depends on and produce iron-binding siderophores Disk-diffusion method for cefiderocol is standardized to be performed on regular inactivates drug expels -lactams available free iron Mueller-Hinton agar plates Stable against all classes Active against isolates that (A, B, C, and D) of are resistant due to efflux -lactamase Efflux pump 1,9-11 Fe -lactamases, including hydrolysis up-regulation pump up-regulation Gr serine-carbapenemases am -ne and metallo--lactamases ga 9,26 ti (VIM, IMP, and NDM) ve b USFET-0306 02/21 a c Immune cells such as t e r neutrophils i Porin channel a changes Active against pathogens Fe Iron-bound siderophores ™ that have a decrease or change 4 1,9,26 are then actively Thermo Scientific in porin channels Fe Fe Fe Iron transported into the cell ™ Photograph used courtesy of Thermo Fisher limit drug access 2 In response to infection, to allow growth Sensititre MIC Plates Scientific; copying prohibited. Fe host cells produce iron-binding Fe lactoferrin to sequester iron Plates including cefiderocol (MIC range: 0.03–32 µg/mL): • Visit www.thermofisher.com/AST or email your local representative at LEARN MORE AT [email protected] to order Fetroja.com • Catalog numbers: MDRGN2F, MDRGNX2F (with colistin)–10 plates/box Exact mechanisms Fe and transporters IMPORTANT SAFETY INFORMATION (continued) Lactoferrin may vary across Standard Sensititre Mueller-Hinton broth is used for inoculation Bacterial siderophore pathogens WARNINGS AND PRECAUTIONS (continued) INDICATIONS Development of Drug-Resistant Bacteria Fetroja® (cefiderocol) is indicated in patients 18 years of age or older for the treatment of complicated Prescribing Fetroja in the absence of a proven or strongly suspected bacterial infection or a prophylactic urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible Gram-negative USFET-0306 02/21 indication is unlikely to provide benefit to the patient and increases the risk of the development of drug- microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and resistant bacteria. Enterobacter cloacae complex. ADVERSE REACTIONS Fetroja is indicated in patients 18 years of age or older for the treatment of hospital-acquired bacterial Laboratory Specialists, Inc. (LSI) The most common adverse reactions occurring in (≥2%) of patients receiving Fetroja compared to imipenem/ pneumonia and ventilator-associated bacterial pneumonia, caused by the following susceptible Gram- cilastatin in the cUTI trial were: diarrhea (4% vs 6%), infusion site reactions (4% vs 5%), constipation (3% negative microorganisms: Acinetobacter baumannii complex, Escherichia coli, Enterobacter cloacae Panel of Isolates vs 4%), rash (3% vs <1%), candidiasis (2% vs 3%), cough (2% vs <1%), elevations in liver tests (2% vs <1%), complex, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens. headache (2% vs 5%), hypokalemia (2% vs 3%), nausea (2% vs 4%), and vomiting (2% vs 1%). The most USAGE • Visit www.labspec.org, email your local representative at [email protected], common adverse reactions occurring in (≥4%) of patients receiving Fetroja compared to meropenem in the HABP/VABP trial were: elevations in liver tests (16% vs 16%), hypokalemia (11% vs 15%), diarrhea (9% vs 9%), To reduce the development of drug-resistant bacteria and maintain the effectiveness of Fetroja and or call (440) 835-4458 to order hypomagnesemia (5% vs <1%), and atrial fibrillation (5% vs 3%). other antibacterial drugs, Fetroja should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. CONTRAINDICATIONS Shionogi has collaborated with LSI to develop a panel of isolates for laboratories to Fetroja is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or other IMPORTANT SAFETY INFORMATION beta-lactam antibacterial drugs, or any other component of Fetroja. perform verification and validation CONTRAINDICATIONS Please see additional Important Safety Information throughout and enclosed Full Prescribing Fetroja is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or Information for Fetroja in pocket. other beta-lactam antibacterial drugs, or any other component of Fetroja. Please see additional Important Safety Information throughout and enclosed Full Prescribing © 2021 Shionogi Inc. Florham Park, NJ 07932. All Rights Reserved. Fetroja is a registered trademark of Shionogi & Co., Ltd. Osaka, Japan. All other trademarks are the property of their respective owners. USFET-0306 02/21 PleaseInformation see additional for Fetroja Important in pocket. Safety Information throughout and Full Prescribing Information

USFET-0306 02/21 for Fetroja located at the end. 1

2019;53(2):177-184. Study). (SIDERO-WT-2014 isolates metallo-ϐ-lactamase-producing Int J Antimicrob Agents. Agents. Antimicrob J Int

multidrug-resistant of challenge Global RA. Bonomo PN, Rather BK, Becker KM, Hujer AM, Hujer Antimicrob Agents Chemother. Agents Antimicrob baumannii. Acinetobacter

23. Perez F, F, Perez 2011;66(10):2298-2307. 2007–09. in USA the from non-fermenters and Enterobacteriaceae in mechanisms resistance J Antimicrob Chemother. Chemother. Antimicrob J

fam. nov., nov., fam. nov., fam. nov., fam. , families the into divided nov. ord. for proposal Yersiniaceae Pectobacteriaceae Erwiniaceae Enterobacteriaceae Enterobacterales

17. : : ‘ the of taxonomy and phylogeny Genome-based RS. Gupta S, Naushad S, Alnajar M, Adeolu doi:10.1186/s13613-015-0061-0. 2015;5(1):61. Enterobacteriales’

16. . . bacilli. Gram-negative in resistance antimicrobial of Mechanisms F. Barbier PL, Woerther É, Ruppé 2012;25(1):2-41. . Ann Intensive Care Intensive Ann Rev Microbiol Clin

13. . . ϐ-lactamases. on perspectives present and Past K. Bush 2007;20(3):440-458. . ϐ-lactamases. versatile Antimicrob Agents Chemother Agents Antimicrob Rev Microbiol Clin

11. , and and , , against cefiderocol of Activity J. Quale D, Landman Z, Khan A, Iregui 2020;26(7):1-5. . Pseudomonas aeruginosa Pseudomonas Enterobacterales Resist Drug Microb

10. Iregui A, Khan Z, Landman D, D, Landman Z, Khan A, Iregui doi:10.1128/AAC.01454-17. 2018;62(1). . bacteria. Gram-negative against cephalosporin, Antimicrob Agents Chemother Agents Antimicrob

. 2016;60(12): . . against activity antibacterial for systems transporter iron ferric utilizes cefiderocol Antimicrob Agents Chemother Agents Antimicrob aeruginosa Pseudomonas

2. 1. References: Ellermann M, Arthur JC. Siderophore-mediated iron acquisition acquisition iron Siderophore-mediated JC. Arthur M, Ellermann 2020. Inc.; Shionogi NJ: Park, Florham insert]. [package (cefiderocol) Fetroja

• CLSI breakpoints for Fetroja can be found in CLSI M100 CLSI in found be can Fetroja for breakpoints CLSI •

• FDA breakpoints for Fetroja can be found at FDA/STIC at found be can Fetroja for breakpoints FDA •

• Breakpoints are based on a dosage regimen of 2 grams every 8 hours administered over 3 hours 3 over administered hours 8 every grams 2 of regimen dosage a on based are Breakpoints •

susceptibility testing susceptibility

FDA and CLSI recommendations for Fetroja antibiotic antibiotic Fetroja for recommendations CLSI and FDA

(Total iron, mg/L) iron, (Total

1.02 10.02 0.52 0.32 0.20 0.12 0.07 0.05 0.03 0.02

available Mueller-Hinton broth Mueller-Hinton available

7,18

prepared using commercially commercially using prepared 0.2

• ID-CAMHB media can be be can media ID-CAMHB • P aeruginosa MIC (μg/mL)

0.4

MIC testing MIC

19 (~0.2 μg/mL) (~0.2 μg/mL) (≤0.03

dilution method for Fetroja Fetroja for method dilution 0.6

CAMHB ID-CAMHB

media for the microbroth microbroth the for media

0.8

≤ 0.03 μg/mL) μg/mL) 0.03 content (iron

CLSI has approved ID-CAMHB ID-CAMHB approved has CLSI 1

with additional iron additional with

ID-CAMHB ID-CAMHB ID-CAMHB CAMHB

1.2

Cefiderocol (siderophore + porin uptake) porin + (siderophore Cefiderocol

Concentration of iron plays a critical role in the determination of Fetroja MICs Fetroja of determination the in role critical a plays iron of Concentration

leading to active Fetroja uptake Fetroja active to leading

18 During infection, human plasma has very low available iron, iron, available low very has plasma human infection, During FetrojaFetroja—a overcomes unique siderophore 3 major mechanisms cephalosporin of carbapenemFetroja is a siderophore resistance bound to cephalosporin, and uses iron to actively enter bacterial cells, along with passive porin entry1 Fetroja passively and actively enters cells…1,4 ...and overcomes resistance

C-7 Activeside chain transport allows for an additional Overcomes porin channel changesC-3 by side chainOvercomes efflux pump • Enhancesmethod stability of entry against into bacterial ϐ-lactamases cells7 entering through the iron transport• system Increases1,4 antibacterialup-regulation activity1,9-11 and stability against ϐ-lactamases5,6 OTHER S S O O LACTAMS Fetroja H IRON H H2N H2N N N N 7 S N 7 S Fe 3 + + N N N N 3 N CH O O O O 3

PORIN OH CH CHANNEL O FeO IRON TRANSPORT SYSTEM 3 O O ALTERED PORIN CHANNEL O Ceftazidime Cefepime Catechol moiety OUTER MEMBRANE • Provides additional stability against For additional information, S O ϐ-lactamases PERIPLASM H2N H N N 7 S visit Fetroja.com O CILACTAM • Binds to free iron 3 + PASSIVE DIFFUSION N N FetrojaN DEGRADATIONOH ACTIVE TRANSPORTO O N Stable against Maintains activity H 3+ Fe all classes of despite efflux pump Fe OH O O OH ϐ-lactamases up-regulation1,9-11 4 O Adapted from Zhanel et al. Cefiderocol 1 PEPTIDOGLYCAN (A, B, C, and D)

EFFLUX PUMP • Fetroja acts like a “Trojan horse” to trick the bacteria to actively uptake Fetroja via iron transport systems1,4,7,8 - A study has demonstrated that Fetroja forms a chelating complex with iron, which is actively 7 INNER MEMBRANEtransported into cells via iron transportersFe - Like other ϐ-lactams, Fetroja also enters bacterial cells through passive diffusion via porin channels PENICILLINBINDING PROTEINS Adapted from Zhanel et al. • Upon bacterial cell entry, Fetroja exerts bactericidal activity by inhibiting cell wall biosynthesis • Thethrough unique binding structure to penicillin-binding of Fetroja allows proteins it to remain (PBPs) stable1,4 against all classes of ϐ-lactamases1,5 - In studies evaluating in vitro bactericidal activity, Fetroja demonstrated binding affinity for PBP3 • Fetroja is able to overcome porin channel changes as it also enters through the active iron in Escherichia coli and Pseudomonas aeruginosa9 transport system1,4,9 For additional information, visit Fetroja.com • Fetroja is active against isolates that are resistant due to efflux pump up-regulation1,9-11

IMPORTANT SAFETY INFORMATION (continued) IMPORTANTWARNINGS AND SAFETY PRECAUTIONS INFORMATION (continued) (continued) IncreaseWARNINGS in All-Cause AND PRECAUTIONS Mortality in Patients with Carbapenem-Resistant Gram-Negative Bacterial Infections (continued) Increase in All-Cause Mortality in Patients with Carbapenem-Resistant Gram-Negative TheBacterial increase Infections in all-cause mortality occurred in patients treated for nosocomial pneumonia, bloodstream infections, or sepsis. The 28-Day all-cause mortality was higher in patients treated with Fetroja than inAn patients increase treated in all-cause with BAT mortality [25/101 was (24.8%) observed vs 9/49 in patients(18.4%), treatmenttreated with difference Fetroja as 6.4%, compared 95% CI to(-8.6, best 19.2)].available All-cause therapy mortality (BAT) in aremained multinational, higher randomized, in patients treated open-label with Fetrojatrial in criticallythan in patients ill patients treated with with BATcarbapenem-resistant through Day 49 [34/101 Gram-negative (33.7%) vs 10/49bacterial (20.4%), infections treatment (NCT02714595). difference 13.3%, Patients 95% with CI nosocomial(-2.5, 26.9)]. Generally,pneumonia, deaths bloodstream were in patientsinfections, with sepsis, infections or cUTI caused were by included Gram-negative in the trial. organisms, BAT regimens including varied non- fermentersaccording to such local as practices Acinetobacter and consisted baumannii of complex,1 to 3 antibacterial Stenotrophomonas drugs with maltophilia activity against, and Pseudomonas Gram-negative aeruginosabacteria. Most, and of were the BATthe result regimens of worsening contained or colistin. complications of infection, or underlying comorbidities. ThePlease cause see of additional the increase Important in mortality Safety has Information not been established. throughout and enclosed Full Prescribing For additional information, CloselyInformation monitor for Fetrojathe clinical in pocket. response to therapy in patients with cUTI and HABP/VABP. Please see additional Important Safety Information throughout and Full Prescribing Information visit Fetroja.com 2for Fetroja located at the end. 3 2 Fetroja overcomes 3 major mechanisms of Fetrojacarbapenem overcomes resistance 3 major mechanisms of carbapenem resistance Fetroja passively and actively enters cells…1,4 ...and overcomes resistance Fetroja passively and actively enters cells…1,4 ...and overcomes resistance

Active transport allows for an additional Overcomes porin channel changes by Overcomes efflux pump method of entry into bacterial cells7 entering through the iron transport system1,4 up-regulation1,9-11 Active transport allows for an additional Overcomes porin channel changes by Overcomes efflux pump OTHERmethod of entry into bacterial cells7 entering through the iron transport system1,4 up-regulation1,9-11 LACTAMS Fetroja IRON OTHER Fe LACTAMS Fetroja IRON PORIN Fe CHANNEL Fe IRON TRANSPORT SYSTEM ALTERED PORIN CHANNEL PORIN CHANNEL Fe IRON TRANSPORT SYSTEM ALTERED PORIN CHANNEL OUTER MEMBRANE

OUTERPERIPLASM MEMBRANE LACTAM PERIPLASM PASSIVE DIFFUSION ACTIVE TRANSPORT Fetroja DEGRADATION Stable against Maintains activity

Fe LACTAM all classes of despite efflux pump PASSIVE DIFFUSION ACTIVE TRANSPORT Fetroja DEGRADATION ϐStable-lactamases against Maintainsup-regulation activity1,9-11 all classes of 1 despite efflux pump PEPTIDOGLYCAN Fe (A, B, C, and D) ϐ-lactamases up-regulation1,9-11 1 PEPTIDOGLYCAN (A, B, C, and D) EFFLUX PUMP

EFFLUX PUMP

INNER MEMBRANE Fe

INNER MEMBRANE Fe PENICILLINBINDING PROTEINS Adapted from Zhanel et al.

PENICILLINBINDING PROTEINS Adapted from Zhanel et al. • The unique structure of Fetroja allows it to remain stable against all classes of ϐ-lactamases1,5 1,5 • FetrojaThe unique is able structure to overcome of Fetroja porin allows channel it to changes remain stableas it also against enters all through classes the of ϐ-lactamases active iron • transportFetroja is ablesystem to 1,4,9overcome porin channel changes as it also enters through the active iron 1,4,9 • transportFetroja is activesystem against isolates that are resistant due to efflux pump up-regulation1,9-11 • Fetroja is active against isolates that are resistant due to efflux pump up-regulation1,9-11 IMPORTANT SAFETY INFORMATION (continued) IMPORTANTWARNINGS AND SAFETY PRECAUTIONS INFORMATION (continued) (continued) IncreaseWARNINGS in All-Cause AND PRECAUTIONS Mortality in (continued) Patients with Carbapenem-Resistant Gram-Negative IncreaseBacterial in Infections All-Cause (continued) Mortality in Patients with Carbapenem-Resistant Gram-Negative BacterialThe increase Infections in all-cause (continued) mortality occurred in patients treated for nosocomial pneumonia, bloodstream Theinfections, increase or insepsis. all-cause The 28-Daymortality all-cause occurred mortality in patients was treated higher for in patientsnosocomial treated pneumonia, with Fetroja bloodstream than infections,in patients ortreated sepsis. with The BAT 28-Day [25/101 all-cause (24.8%) mortality vs 9/49 (18.4%), was higher treatment in patients difference treated 6.4%, with 95%Fetroja CI (-8.6,than in19.2)]. patients All-cause treated mortality with BAT remained [25/101 (24.8%)higher invs patients 9/49 (18.4%), treated treatment with Fetroja difference than in 6.4%, patients 95% treated CI (-8.6, with 19.2)].BAT through All-cause Day mortality 49 [34/101 remained (33.7%) vshigher 10/49 in (20.4%), patients treatment treated with difference Fetroja 13.3%,than in 95%patients CI (-2.5, treated 26.9)]. with BATGenerally, through deaths Day 49were [34/101 in patients (33.7%) with vs 10/49infections (20.4%), caused treatment by Gram-negative difference 13.3%, organisms, 95% CI including (-2.5, 26.9)]. non- Generally,fermenters deaths such as were Acinetobacter in patients baumanniiwith infections complex, caused Stenotrophomonas by Gram-negative maltophilia organisms,, and including Pseudomonas non- fermentersaeruginosa, andsuch were as Acinetobacter the result of baumanniiworsening complex, or complications Stenotrophomonas of infection, maltophilia or underlying, and comorbidities.Pseudomonas aeruginosaThe cause ,of and the were increase the result in mortality of worsening has not or been complications established. of infection, or underlying comorbidities. TheClosely cause monitor of the theincrease clinical in responsemortality tohas therapy not been in patientsestablished. with cUTI and HABP/VABP. CloselyPlease seemonitor additional the clinical Important response Safety to therapyInformation in patients throughout with cUTI and andFull HABP/VABP. Prescribing Information 3 for Fetroja located at the end. 3 3 Fetroja overcomeshas activity 3 inmajor the presencemechanisms of a of variety carbapenemof carbapenem-resistant resistance mechanisms1,10-13

Fetroja passively and actively enters cells…1,4 ...and overcomes resistance Resistance mechanism Description In vitro activity

FetrojaActive istransport stable allows against for an all additional known classes Overcomesof -lactamases porin channel (bold=carbapenemase) changes by Overcomes efflux pump method of entry into bacterial cells7 entering through the iron transport system1,4 up-regulation1,9-11

ClassOTHER A KPC, TEM, SHV, CTX-M, GES, L2 LACTAMS Fetroja IRON Class B (Metallo) IMP, VIM,Fe NDM, L1 PORIN ClassCHANNEL C Fe AmpC,IRON TRANSPORT CMY SYSTEM ALTERED PORIN CHANNEL

OUTERClass MEMBRANE D OXA-23, OXA-24/40, OXA-48, OXA-51, OXA-58

PERIPLASM Other mechanisms of carbapenem resistance LACTAM PASSIVE DIFFUSION ACTIVE TRANSPORT Fetroja DEGRADATION Stable against Maintains activity

Fe all classes of despite efflux pump Porin channel deletions OmpK35/36 porin deletiona, OprDϐ-lactamases porin deletionb up-regulation1,9-11 1 PEPTIDOGLYCAN (A, B, C, and D)

MexAB-OprM, MexCD-OprJ, MexEF-OprN, EFFLUX PUMP Efflux pump up-regulation and MexXYb

a Present in K pneumoniae. b PresentINNER MEMBRANE in P aeruginosa. Fe

IMPORTANTPENICILLINBINDING SAFETY PROTEINSINFORMATION (continued) Adapted from Zhanel et al. WARNINGS AND PRECAUTIONS (continued) Hypersensitivity• The unique structure Reactions of Fetroja allows it to remain stable against all classes of ϐ-lactamases1,5 Serious• Fetroja and is ableoccasionally to overcome fatal hypersensitivity porin channel (anaphylactic)changes as it reactionsalso enters and through serious theskin active reactions iron have been reported in patients1,4,9 receiving beta-lactam antibacterial drugs. Hypersensitivity was observed in Fetroja-treatedtransport system patients in clinical trials. These reactions are more likely to occur in individuals with a history of beta-lactam hypersensitivity and/or a history of sensitivity to multiple allergens. There have • Fetroja is active against isolates that are resistant due to efflux pump up-regulation1,9-11 been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins. BeforeIMPORTANT therapy withSAFETY Fetroja INFORMATION is instituted, inquire (continued) about previous hypersensitivity reactions to cephalosporins, penicillins,WARNINGS or AND other PRECAUTIONS beta-lactam antibacterial (continued) drugs. Discontinue Fetroja if an allergic reaction occurs. IncreaseClostridioides in All-Cause difficile-associated Mortality in Diarrhea Patients (CDAD)with Carbapenem-Resistant Gram-Negative ClostridioidesBacterial Infections difficile-associated (continued) diarrhea (CDAD) has been reported for nearly all systemic antibacterial Theagents, increase including in all-cause Fetroja. CDADmortality may occurred range in inseverity patients from treated mild fordiarrhea nosocomial to fatal pneumonia, colitis. Treatment bloodstream with infections,antibacterial or agents sepsis. alters The 28-Day the normal all-cause flora mortalityof the colon was and higher may inpermit patients overgrowth treated withof C. Fetrojadifficile. than Carefulin patients medical treated history with BAT is necessary [25/101 (24.8%) because vs CDAD9/49 (18.4%), has been treatment reported difference to occur more 6.4%, than 95% 2CI months (-8.6, after19.2)]. the All-cause administration mortality of remained antibacterial higher agents. in patients treated with Fetroja than in patients treated with BAT through Day 49 [34/101 (33.7%) vs 10/49 (20.4%), treatment difference 13.3%, 95% CI (-2.5, 26.9)]. Generally,If CDAD is deathssuspected were or in confirmed, patients with antibacterial infections drugscaused not by directedGram-negative against organisms, C. difficile may including need tonon- be fermentersdiscontinued. such Manage as Acinetobacter fluid and electrolyte baumannii levels complex, as appropriate, Stenotrophomonas supplement maltophilia protein, and intake, Pseudomonas monitor aeruginosaantibacterial, and treatment were the of result C. difficile of worsening, and institute or complications surgical evaluation of infection, as clinically or underlying indicated. comorbidities. ThePlease cause see of additional the increase Important in mortality Safety has Information not been established. throughout and enclosed Full Prescribing CloselyPleaseInformation seemonitor additional for Fetrojathe clinical Important in pocket. response Safety to therapyInformation in patients throughout with cUTI and andFull HABP/VABP. Prescribing Information 4for Fetroja located at the end. 3 4 Fetroja antimicrobial spectrum1 FetrojaIn vitro activity overcomes does not necessarily 3 major correlate mechanisms with clinical efficacy. of carbapenem resistance Activity in both in vitro and in clinical infections Fetroja passively and actively enters cells…1,4 ...and overcomes resistance Fetroja has demonstrated activity against the following Gram-negative bacteria, both in vitro and in clinical infections: Active transport allows for an additional Overcomes porin channel changes by Overcomes efflux pump 7 1,9-11 HABPmethod and VABPof entry into bacterial cells entering throughcUTI the iron transport system1,4 up-regulation OTHER AcinetobacterLACTAMS Fetrojabaumannii complex IRON Escherichia coli Escherichia coli Fe Enterobacter cloacae complex PORIN EnterobacterCHANNEL cloacae complexFe IRON TRANSPORT SYSTEM KlebsiellaALTERED pneumoniae PORIN CHANNEL Klebsiella pneumoniae Proteus mirabilis OUTER MEMBRANE Pseudomonas aeruginosa Pseudomonas aeruginosa PERIPLASM Serratia marcescens LACTAM PASSIVE DIFFUSION ACTIVE TRANSPORT Fetroja DEGRADATION Stable against Maintains activity

Fe all classes of despite efflux pump ϐ-lactamases up-regulation1,9-11 (A, B, C, and D)1 PEPTIDOGLYCANIn vitro activity

Fetroja demonstrated in vitro activity against the following Gram-negative bacteria,EFFLUX but PUMP the clinical significance is unknown: • At least 90% of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC)

INNER lessMEMBRANE than or equal to the susceptibleFe breakpoint for Fetroja Achromobacter spp Klebsiella oxytoca PENICILLINBINDING PROTEINS Adapted from Zhanel et al. Burkholderia cepacia complex Morganella morganii • CitrobacterThe unique freundii structure complex of Fetroja allows it to remainProteus stable vulgarisagainst all classes of ϐ-lactamases1,5 • CitrobacterFetroja is able koseri to overcome porin channel changesProvidencia as it also entersrettgeri through the active iron Klebsiellatransport aerogenessystem1,4,9 Stenotrophomonas maltophilia • Fetroja is active against isolates that are resistant due to efflux pump up-regulation1,9-11 Bacteria added as part of FDA approval for HABP/VABP indication. IMPORTANT SAFETY INFORMATION (continued) WARNINGS AND PRECAUTIONS (continued) IncreaseIMPORTANT in All-Cause SAFETY Mortality INFORMATION in Patients (continued) with Carbapenem-Resistant Gram-Negative Bacterial Infections (continued) WARNINGS AND PRECAUTIONS (continued) TheSeizures increase and in Other all-cause Central mortality Nervous occurred System in (CNS) patients Adverse treated Reactions for nosocomial pneumonia, bloodstream infections, or sepsis. The 28-Day all-cause mortality was higher in patients treated with Fetroja than inCephalosporins, patients treated including with BAT Fetroja, [25/101 have (24.8%) been vs implicated 9/49 (18.4%), in triggeringtreatment seizures.difference Nonconvulsive 6.4%, 95% CI (-8.6,status 19.2)].epilepticus All-cause (NCSE), mortality encephalopathy, remained highercoma, inasterixis, patients neuromuscular treated with Fetroja excitability, than in and patients myoclonia treated have with BATbeen through reported Day with 49 cephalosporins[34/101 (33.7%) particularlyvs 10/49 (20.4%), in patients treatment with adifference history of 13.3%, epilepsy 95% and/or CI (-2.5, when 26.9)]. Generally,recommended deaths dosages were in of patients cephalosporins with infections were exceeded caused by due Gram-negative to renal impairment. organisms, Adjust including Fetroja non- fermentersdosing based such on creatinineas Acinetobacter clearance. baumannii Anticonvulsant complex, Stenotrophomonastherapy should be maltophiliacontinued ,in and patients Pseudomonas with aeruginosaknown seizure, and disorders. were the result If CNS of adverse worsening reactions or complications including seizures of infection, occur, or patientsunderlying should comorbidities. undergo a Theneurological cause of theevaluation increase to in determine mortality whetherhas not been Fetroja established. should be discontinued. CloselyPlease seemonitor additional the clinical Important response Safety to therapyInformation in patients throughout with cUTI and andFull HABP/VABP. Prescribing Information 5 for Fetroja located at the end. 3 5 FetrojaHigh-priority overcomes and challenging 3 major mechanisms pathogens of are highly carbapenem susceptible to resistance Fetroja in vitro14

InFe tthisroja passi study,vely susceptibilityand actively enter ofs c ell>38,000s…1,4 Gram-negative.. .andclinical overcomes isolates resistan fromce multiple countries (2013-2018) was tested against Fetroja In vitro activity does not necessarily correlate with clinical efficacy. Active transport allows for an additional Overcomes porin channel changes by Overcomes efflux pump method of entry into bacterial cells7 entering through the iron transport system1,4 up-regulation1,9-11 a OTHER Enterobacterales (n=25,995) LACTAMS Fetroja Overall IRON 100% a Fe Enterobacterales (n=814) carbapenem-non-susceptible 97% PORIN CHANNEL Fe IRON TRANSPORT SYSTEM ALTERED PORIN CHANNEL P aeruginosaa OUTER MEMBRANE (n=6213) Overall 98%

PERIPLASM a P aeruginosa (n=1416) carbapenem-non-susceptible LACTAM 95% PASSIVE DIFFUSION ACTIVE TRANSPORT Fetroja DEGRADATION Stable against Maintains activity

Fe all classes of despite efflux pump a ϐ-lactamases up-regulation1,9-11 A baumannii complex (n=4185) (A, B, C, and D)1 PEPTIDOGLYCAN Overall 90% a A baumannii complex (n=2274) EFFLUX PUMP carbapenem-non-susceptible 85%

b S maltophilia (n=1565) Overall 100% 15,16 INNER MEMBRANE (inherently carbapenem-resistant) Fe

0 20 40 60 80 100 PENICILLINBINDING PROTEINS PERCENT Adapted from Zhanel et al. In a phylogenetic reclassification performed in 2016, the nomenclature of Enterobacterales was proposed, which includes formerly •established The unique Enterobacteriaceae structure of family Fetroja and otherallows genera it to such remain as Proteus stable spp, againstProvidencia all spp, classes Photorhabdus of ϐ-lactamases spp, and Serratia1,5 spp.17 14 •In Fetroja vitro susceptibility is able to overcome study porin design channel changes as it also enters through the active iron Clinicaltransport isolates system of Gram-negative1,4,9 bacteria were collected from 4 global surveillance studies (SIDERO-WT-2014, SIDERO-WT-2015, SIDERO-WT-2016, and SIDERO-WT-2018) that included Enterobacterales* and non-fermenter strains. The global surveillance † •study Fetroja (Proteeae is active) collected against clinical isolates isolates fromthat 2013-2016, are resistant and were due tested to efflux centrally pump (IHMA up-regulation Inc., Schaumburg,1,9-11 IL, USA). Fetroja MICs were determined by microbroth dilution using iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) as approved by the Clinical and Laboratory Standards Institute (CLSI) subcommittee on antimicrobial susceptibility testing in January 2016. IMPORTANTFDA breakpoints were SAFETY used for INFORMATIONEnterobacterales MIC (continued) ≤4 μg/mL, P aeruginosa MIC ≤1 μg/mL, and A baumannii complex‡ MIC ≤1 μg/mL, whereas CLSI investigational breakpoint was used for S maltophilia MIC ≤4 μg/mL. Carbapenem-non-susceptible strain wasWARNINGS defined as ANDmeropenem PRECAUTIONS MIC ≥2 μg/mL (continued) for Enterobacterales strains (including Proteeae) and MIC ≥4 μg/mL for IncreaseP aeruginosa in and All-Cause A baumannii Mortality complex. in Patients with Carbapenem-Resistant Gram-Negative Bacterial Infections (continued) aFDA breakpoints used for Enterobacterales MIC ≤4 μg/mL, P aeruginosa MIC ≤1 μg/mL, and A baumannii complex MIC ≤1 μg/mL. ThebCLSI investigationalincrease in breakpoint all-cause used mortality for S maltophilia occurred MIC ≤4 μg/mL. in patients treated for nosocomial pneumonia, bloodstream *Escherichia coli, Klebsiella pneumoniae, other Klebsiella spp, Enterobacter spp, Serratia spp, and Citrobacter spp. infections,†Morganella morganii or sepsis., Proteus mirabilis The 28-Day, Proteus vulgarisall-cause, and Providencia mortality rettgeri was. higher in patients treated with Fetroja than in‡A baumannii patients complex treated consists with of ABAT baumannii, [25/101 A calcoaceticus, (24.8%) A vsdijkshoorniae, 9/49 (18.4%), A nosocomialis, treatment A pittii, and difference A seifertii. 6.4%, 95% CI (-8.6, 19.2)]. All-cause mortality remained higher in patients treated with Fetroja than in patients treated with BAT through Day 49 [34/101 (33.7%) vs 10/49 (20.4%), treatment difference 13.3%, 95% CI (-2.5, 26.9)]. Generally, deathsFetroja were has in no patients clinically with relevant infections in vitrocaused activity by Gram-negative against most organisms, Gram-positive including non- fermenters such as Acinetobacter baumanniibacteria andcomplex, anaerobic Stenotrophomonas bacteria9 maltophilia, and Pseudomonas aeruginosa, and were the result of worsening or complications of infection, or underlying comorbidities. ThePlease cause see of additional the increase Important in mortality Safety has Information not been established. throughout and enclosed Full Prescribing CloselyPleaseInformation seemonitor additional for Fetrojathe clinical Important in pocket. response Safety to therapyInformation in patients throughout with cUTI and andFull HABP/VABP. Prescribing Information 6for Fetroja located at the end. 3 6 Available susceptibility testing methods for Fetroja A closer look into Fetroja for microbiologists Available susceptibility testing methods for Fetroja A closer look into Fetroja for microbiologists ® Fetroja overcomes the 3 major, often coexisting, Gram-negative Fetroja® (cefiderocol) ™ Fetroja overcomes the 31,10,11,22-24 major, often coexisting, Gram-negative Fetroja (cefiderocol) ™ resistance mechanisms1,10,11,22-24 FetrojaThe world’s (cefiderocol) only siderophore cephalosporin—uses iron HardyDisk™ resistance mechanisms1,10,11,22-24 The world’s only siderophore cephalosporin—uses iron HardyDisk resistance mechanisms The world’s only siderophore cephalosporin—uses iron 1 HardyDisk to gain bacterial cell entry, along with passive porin entry1 Fetroja remains active in the presence of all these mechanisms, which often coexist in to gain bacterial cell entry, along with passive porin entry1 Fetroja remains active in the presence of all these mechanisms, which often1, 11, 22-25 coexist in to gain bacterial cell entry, along with passive porin entry Cefiderocol 30 µg disk: hard-to-treat pathogens such as A baumannii complex and P aeruginosa1, 11, 22-25 2,3 Cefiderocol 30 µg disk: hard-to-treat pathogens suchFetroja as remains A baumannii active against complex all of these mechanismsand P aeruginosa1, 11, 22-25 To survive in the host environment, bacteria use siderophores to actively uptake iron2,3 Cefiderocol 30 µg disk: hard-to-treat pathogens suchFetroja as remains A baumannii active against complex all of these mechanismsand P aeruginosa To survive in the host environment, bacteria use siderophores to actively uptake iron2,3 • Visit www.hardydiagnostics.com or call 1-800-266-2222 to order Fetroja remains active against all of these mechanisms To survive in the host environment, bacteria use siderophores to actively uptake iron • Visit www.hardydiagnostics.com or call 1-800-266-2222 to order • Catalog numbers: single pack, Z9431; 5-pack, Z9435 Fetroja Fetroja Bacteria 1 Bacterial growth 3 Bacteria respond to low iron concentration • Catalog numbers: single pack, Z9431; 5-pack, Z9435 Bacteria 1 dependsBacterial on growth 3 andBacteria produce respond iron-binding to low iron siderophores concentration Fetroja 1 dependsBacterial on growth 3 Bacteria respond to low iron concentration Disk-diffusion method for cefiderocol is standardized to be performed on regular inactivates drug expels -lactams Bacteria available free iron and produce iron-binding siderophores Disk-diffusion method for cefiderocol is standardized to be performed on regular inactivates drug expels -lactams availabledepends on free iron and produce iron-binding siderophores Disk-diffusionMueller-Hinton method agar plates for cefiderocol is standardized to be performed on regular inactivatesStable against all classesdrug Activeexpels against -lactams isolates that available free iron Mueller-Hinton agar plates (A,Stable B, C, against and D) allof classes Activeare resistant against dueisolates to efflux that Stable against all classes -lactamase Efflux pump Active against isolates that Mueller-Hinton agar plates (A,-lactamases, B, C, and D) includingof -lactamase Efflux pump arepump resistant up-regulation due to efflux1,9-11 Fe (A, B, C, and D) of hydrolysis up-regulation are resistant due to efflux1,9-11 Fe Gr serine-carbapenemases-lactamases, including -lactamase Efflux pump pump up-regulation G am -lactamases, including hydrolysis up-regulation pump up-regulation1,9-11 Fe ram-n andserine-carbapenemases metallo--lactamases hydrolysis up-regulation Gr - eg serine-carbapenemases am ne at (VIM,and metallo- IMP, and-lactamases NDM)9,26 -n ga iv 9,26 eg ti e (VIM,and metallo- IMP, and-lactamases NDM) a ve b USFET-0306 02/21 9,26 tiv a USFET-0306 02/21 (VIM, IMP, and NDM) e b c Immune cells such as a t USFET-0306 02/21 Immune cells such as b c e a t r neutrophils c e i Porin channel Immune cells such as t r a neutrophils e i a Porin channel r changes neutrophils i Porin channel Active against pathogens a changes Active against pathogens Fe Iron-bound siderophores changes that have a decrease or change Fe 4 ™ Active against pathogens Iron-bound siderophores 4 that have a decrease or change1,9,26 Fe are then actively Thermo Scientific™ in porin channels Fe Iron-bound siderophores Fe that have a decrease or change1,9,26 Fe are then actively 4 Thermo Scientific™ in porin channels Fe Iron transported into the cell Fe 1,9,26 Fe are then actively Thermo Scientific™ in porin channels Fe Iron transported into the cell Fe Photograph used courtesy of Thermo Fisher limit drug access 2 In response to infection, Fe to allow growth Sensititre™ MIC Plates Photograph used courtesy of Thermo Fisher Fe Iron transported into the cell Scientific; copying prohibited. limit drug access 2 In response to infection, Fe to allow growth Sensititre™ MIC Plates Scientific; copying prohibited. host cells produce iron-binding Fe Photograph used courtesy of Thermo Fisher limit drug access 2 In response to infection, Fe to allow growth Sensititre MIC Plates host cells produce iron-binding Fe Scientific; copying prohibited. lactoferrin to sequester iron Fe lactoferrinhost cells produce to sequester iron-binding iron Plates including cefiderocol (MIC range: 0.03–32 µg/mL): lactoferrin to sequester iron •Plates Visit www.thermofisher.com/AST including cefiderocol or(MIC email range: your local 0.03–32 representative µg/mL): at LEARN MORE AT • Visit www.thermofisher.com/AST or email your local representative at LEARN MORE AT • [email protected] www.thermofisher.com/AST toor orderemail your local representative at Fetroja.comLEARN MORE AT [email protected] to order Fetroja.com Exact mechanisms [email protected] to order Exact mechanisms • Catalog numbers: MDRGN2F, MDRGNX2F (with colistin)–10 plates/box Fetroja.com and transporters • Catalog numbers: MDRGN2F, MDRGNX2F (with colistin)–10 plates/box Fe andExact transporters mechanisms • Catalog numbers: MDRGN2F, MDRGNX2F (with colistin)–10 plates/box Lactoferrin Fe may vary across Standard Sensititre Mueller-Hinton broth is used for inoculation IMPORTANT SAFETY INFORMATION (continued) Lactoferrin Bacterial siderophoreFe mayand transporters vary across IMPORTANT SAFETY INFORMATION (continued) Lactoferrin Bacterial siderophore maypathogens vary across Standard Sensititre Mueller-Hinton broth is used for inoculation WARNINGSIMPORTANT AND SAFETY PRECAUTIONS INFORMATION (continued) (continued) pathogens Standard Sensititre Mueller-Hinton broth is used for inoculation WARNINGS AND PRECAUTIONS (continued) INDICATIONS Bacterial siderophore pathogens WARNINGSDevelopment AND of Drug-Resistant PRECAUTIONS Bacteria(continued) INDICATIONS Development of Drug-Resistant Bacteria FetrojaINDICATIONS® (cefiderocol) is indicated in patients 18 years of age or older for the treatment of complicated DevelopmentPrescribing Fetroja of Drug-Resistant in the absence Bacteria of a proven or strongly suspected bacterial infection or a prophylactic Fetroja® (cefiderocol) is indicated in patients 18 years of age or older for the treatment of complicated Prescribing Fetroja in the absence of a proven or strongly suspected bacterial infection or a prophylactic urinaryFetroja® tract (cefiderocol) infections is (cUTIs),indicated including in patients pyelonephritis 18 years of agecaused or older by the for following the treatment susceptible of complicated Gram-negative USFET-0306 02/21 Prescribingindication is Fetrojaunlikely in to the provide absence benefit of a toproven the patient or strongly and increases suspected the bacterial risk of theinfection development or a prophylactic of drug- urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible Gram-negative USFET-0306 02/21 indication is unlikely to provide benefit to the patient and increases the risk of the development of drug- microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and resistant bacteria. microorganisms:urinary tract infections Escherichia (cUTIs), coli including, Klebsiella pyelonephritis pneumoniae ,caused Proteus by mirabilis the following, Pseudomonas susceptible aeruginosa Gram-negative, and USFET-0306 02/21 resistantindication bacteria. is unlikely to provide benefit to the patient and increases the risk of the development of drug- microorganisms:Enterobacter cloacae Escherichia complex. coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and resistantADVERSE bacteria. REACTIONS Enterobacter cloacae complex. ADVERSE REACTIONS FetrojaEnterobacter is indicated cloacae in complex. patients 18 years of age or older for the treatment of hospital-acquired bacterial The most common adverse reactions occurring in (≥2%) of patients receiving Fetroja compared to imipenem/ Fetroja is indicated in patients 18 years of age or older for the treatment of hospital-acquired bacterial Laboratory Specialists, Inc. (LSI) TheADVERSE most common REACTIONS adverse reactions occurring in ( 2%) of patients receiving Fetroja compared to imipenem/ pneumonia and ventilator-associated bacterial pneumonia, caused by the following susceptible Gram- Laboratory Specialists, Inc. (LSI) cilastatin in the cUTI trial were: diarrhea (4% vs 6%),≥ infusion site reactions (4% vs 5%), constipation (3% pneumoniaFetroja is indicated and ventilator-associated in patients 18 years bacterial of age or pneumonia, older for the caused treatment by the of following hospital-acquired susceptible bacterial Gram- cilastatinThe most incommon the cUTI adverse trial were: reactions diarrhea occurring (4% vs 6%),in (≥ 2%)infusion of patients site reactions receiving (4% Fetroja vs 5%), compared constipation to imipenem/ (3% negative microorganisms: Acinetobacter baumannii complex, Escherichia coli, Enterobacter cloacae Laboratory Specialists, Inc. (LSI) vs 4%), rash (3% vs <1%), candidiasis (2% vs 3%), cough (2% vs <1%), elevations in liver tests (2% vs <1%), negativepneumonia microorganisms: and ventilator-associated Acinetobacter bacterial baumannii pneumonia, complex, caused Escherichia by the coli following, Enterobacter susceptible cloacae Gram- Panel of Isolates vscilastatin 4%), rash in the (3% cUTI vs <1%), trial were:candidiasis diarrhea (2% (4% vs 3%), vs 6%), cough infusion (2% vs site <1%), reactions elevations (4% vsin liver5%), testsconstipation (2% vs <1%),(3% complex, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens. Panel of Isolates headache (2% vs 5%), hypokalemia (2% vs 3%), nausea (2% vs 4%), and vomiting (2% vs 1%). The most negativecomplex, microorganisms: Klebsiella pneumoniae Acinetobacter, Pseudomonas baumannii aeruginosa complex,, and Escherichia Serratia marcescens coli, Enterobacter. cloacae Panel of Isolates headachevs 4%), rash (2% (3% vs vs5%), <1%), hypokalemia candidiasis (2% (2% vs vs 3%), 3%), nausea cough (2% (2% vs vs 4%), <1%), and elevations vomiting in (2% liver vs tests 1%). (2%The vsmost <1%), complex, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens. headachecommon adverse (2% vs 5%), reactions hypokalemia occurring (2% in vs(≥ 4%)3%), of nausea patients (2% receiving vs 4%), andFetroja vomiting compared (2% vs to 1%).meropenem The most in the USAGE • Visit www.labspec.org, email your local representative at [email protected], common adverse reactions occurring in (≥4%) of patients receiving Fetroja compared to meropenem in the ToUSAGE reduce the development of drug-resistant bacteria and maintain the effectiveness of Fetroja and • Visit www.labspec.org, email your local representative at [email protected], commonHABP/VABP adverse trial were:reactions elevations occurring in liver in (≥ tests4%) of(16% patients vs 16%), receiving hypokalemia Fetroja (11%compared vs 15%), to meropenem diarrhea (9% in vs the 9%), ToUSAGE reduce the development of drug-resistant bacteria and maintain the effectiveness of Fetroja and • orVisit call www.labspec.org, (440) 835-4458 to email order your local representative at [email protected], HABP/VABP trial were: elevations in liver tests (16% vs 16%), hypokalemia (11% vs 15%), diarrhea (9% vs 9%), other antibacterial drugs, Fetroja should be used only to treat or prevent infections that are proven or or call (440) 835-4458 to order HABP/VABPhypomagnesemia trial were: (5% vs elevations <1%), and in atrial liver testsfibrillation (16% (5%vs 16%), vs 3%). hypokalemia (11% vs 15%), diarrhea (9% vs 9%), otherTo reduce antibacterial the development drugs, Fetroja of drug-resistant should be used bacteria only andto treat maintain or prevent the effectiveness infections that of Fetrojaare proven and or or call (440) 835-4458 to order hypomagnesemia (5% vs <1%), and atrial fibrillation (5% vs 3%). strongly suspected to be caused by susceptible bacteria. hypomagnesemiaCONTRAINDICATIONS (5% vs <1%), and atrial fibrillation (5% vs 3%). stronglyother antibacterial suspected drugs,to be caused Fetroja by should susceptible be used bacteria. only to treat or prevent infections that are proven or

FetrojaCONTRAINDICATIONS is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or other strongly suspected to be caused by susceptible bacteria. Shionogi has collaborated with LSI to develop a panel of isolates for laboratories to FetrojaCONTRAINDICATIONS is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or other IMPORTANT SAFETY INFORMATION Shionogi has collaborated with LSI to develop a panel of isolates for laboratories to beta-lactam antibacterial drugs, or any other component of Fetroja. IMPORTANT SAFETY INFORMATION Shionogiperform verificationhas collaborated and validation with LSI to develop a panel of isolates for laboratories to beta-lactamFetroja is contraindicated antibacterial indrugs, patients or any with other a known component history ofof Fetroja.severe hypersensitivity to cefiderocol or other CONTRAINDICATIONSIMPORTANT SAFETY INFORMATION perform verification and validation CONTRAINDICATIONS perform verification and validation beta-lactamPlease see additional antibacterial Important drugs, or Safety any other Information component throughout of Fetroja. and enclosed Full Prescribing Fetroja is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or Please see additional Important Safety Information throughout and enclosed Full Prescribing FetrojaCONTRAINDICATIONS is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or Information for Fetroja in pocket. other beta-lactam antibacterial drugs, or any other component of Fetroja. InformationPlease see additional for Fetroja Important in pocket. Safety Information throughout and enclosed Full Prescribing otherFetroja beta-lactam is contraindicated antibacterial in patients drugs, with or anya known other history component of severe of Fetroja. hypersensitivity to cefiderocol or Information for Fetroja in pocket. otherPlease beta-lactam see additional antibacterial Important drugs, Safety or Information any other component throughout of and Fetroja. enclosed Full Prescribing © 2021 Shionogi Inc. Florham Park, NJ 07932. All Rights Reserved. Fetroja is a registered trademark of Shionogi & Co., Ltd. Osaka, Japan. Please see additional Important Safety Information throughout and enclosed Full Prescribing All© 2021 other Shionogi trademarks Inc. Florham are the property Park, NJ of 07932. their respectiveAll Rights Reserved. owners. USFET-0306 Fetroja is a registered 02/21 trademark of Shionogi & Co., Ltd. Osaka, Japan. PleaseInformation see additional for Fetroja Important in pocket. Safety Information throughout and enclosed Full Prescribing All© 2021 other Shionogi trademarks Inc. Florham are the property Park, NJ of 07932. their respectiveAll Rights Reserved. owners. USFET-0306 Fetroja is a registered 02/21 trademark of Shionogi & Co., Ltd. Osaka, Japan. Information for Fetroja in pocket. USFET-0306 02/21 All other trademarks are the property of their respective owners. USFET-0306 02/21 Information for Fetroja in pocket. USFET-0306 02/21

USFET-0306 02/21

for Fetroja located at the end. end. the at located Fetroja for 7 3

Please see additional Important Safety Information throughout and Full Prescribing Information Information Prescribing Full and throughout Information Safety Important additional see Please 7 2019;53(2):177-184. Study). (SIDERO-WT-2014 isolates metallo-ϐ-lactamase-producing Int J Antimicrob Agents. Agents. Antimicrob J Int

Closely monitor the clinical response to therapy in patients with cUTI and HABP/VABP. and cUTI with patients in therapy to response clinical the monitor Closely

7 2019;53(2):177-184. Study). (SIDERO-WT-2014 isolates metallo-ϐ-lactamase-producing Int J Antimicrob Agents. Agents. Antimicrob J Int cephalosporin, against a recent collection of clinically relevant carbapenem-non-susceptible Gram-negative bacilli, including serine carbapenemase- and and carbapenemase- serine including bacilli, Gram-negative carbapenem-non-susceptible relevant clinically of collection recent a against cephalosporin,

2019;53(2):177-184. Study). (SIDERO-WT-2014 isolates metallo-ϐ-lactamase-producing Int J Antimicrob Agents. Agents. Antimicrob J Int cephalosporin, against a recent collection of clinically relevant carbapenem-non-susceptible Gram-negative bacilli, including serine carbapenemase- and and carbapenemase- serine including bacilli, Gram-negative carbapenem-non-susceptible relevant clinically of collection recent a against cephalosporin,

The cause of the increase in mortality has not been established. established. been not has mortality in increase the of cause The

cephalosporin, against a recent collection of clinically relevant carbapenem-non-susceptible Gram-negative bacilli, including serine carbapenemase- and and carbapenemase- serine including bacilli, Gram-negative carbapenem-non-susceptible relevant clinically of collection recent a against cephalosporin, 26. Kazmierczak KM, Tsuji M, Wise MG, et al. In vitro activity of cefiderocol, a siderophore siderophore a cefiderocol, of activity vitro In al. et MG, Wise M, Tsuji KM, Kazmierczak 2012;25(4):661-681. . resistance. drug in pumps Clin Microbiol Rev Microbiol Clin 25. Fernández L, Hancock REW. Adaptive and mutational resistance: role of porins and efflux efflux and porins of role resistance: mutational and Adaptive REW. Hancock L, Fernández 2009;53(11):4783-4788. . . Antimicrob Agents Chemother Agents Antimicrob aeruginosa

, and were the result of worsening or complications of infection, or underlying comorbidities. comorbidities. underlying or infection, of complications or worsening of result the were and , aeruginosa 26. Kazmierczak KM, Tsuji M, Wise MG, et al. In vitro activity of cefiderocol, a siderophore siderophore a cefiderocol, of activity vitro In al. et MG, Wise M, Tsuji KM, Kazmierczak 2012;25(4):661-681. . resistance. drug in pumps Clin Microbiol Rev Microbiol Clin 25. Fernández L, Hancock REW. Adaptive and mutational resistance: role of porins and efflux efflux and porins of role resistance: mutational and Adaptive REW. Hancock L, Fernández 2009;53(11):4783-4788. . . Antimicrob Agents Chemother Agents Antimicrob aeruginosa 24. Rodríguez-Martínez JM, Poirel L, Nordmann P. Molecular epidemiology and mechanisms of carbapenem resistance in in resistance carbapenem of mechanisms and epidemiology Molecular P. Nordmann L, Poirel JM, Rodríguez-Martínez 2007;51(10):3471-3484. Pseudomonas Pseudomonas

25. Fernández L, Hancock REW. Adaptive and mutational resistance: role of porins and efflux efflux and porins of role resistance: mutational and Adaptive REW. Hancock L, Fernández 2009;53(11):4783-4788. . . Antimicrob Agents Chemother Agents Antimicrob aeruginosa 24. Rodríguez-Martínez JM, Poirel L, Nordmann P. Molecular epidemiology and mechanisms of carbapenem resistance in in resistance carbapenem of mechanisms and epidemiology Molecular P. Nordmann L, Poirel JM, Rodríguez-Martínez 2007;51(10):3471-3484. Pseudomonas Pseudomonas

multidrug-resistant of challenge Global RA. Bonomo PN, Rather BK, Becker KM, Hujer AM, Hujer Antimicrob Agents Chemother. Agents Antimicrob baumannii. Acinetobacter

, and and , complex, as such fermenters Pseudomonas Pseudomonas maltophilia Stenotrophomonas baumannii Acinetobacter

24. Rodríguez-Martínez JM, Poirel L, Nordmann P. Molecular epidemiology and mechanisms of carbapenem resistance in in resistance carbapenem of mechanisms and epidemiology Molecular P. Nordmann L, Poirel JM, Rodríguez-Martínez 2007;51(10):3471-3484. Pseudomonas Pseudomonas multidrug-resistant of challenge Global RA. Bonomo PN, Rather BK, Becker KM, Hujer AM, Hujer Antimicrob Agents Chemother. Agents Antimicrob baumannii. Acinetobacter 23. 2011;66(10):2298-2307. 2011;66(10):2298-2307. 2007–09. in USA the from non-fermenters and Enterobacteriaceae in mechanisms resistance Perez F, F, Perez J Antimicrob Chemother. Chemother. Antimicrob J

Generally, deaths were in patients with infections caused by Gram-negative organisms, including non- including organisms, Gram-negative by caused infections with patients in were deaths Generally, multidrug-resistant of challenge Global RA. Bonomo PN, Rather BK, Becker KM, Hujer AM, Hujer Antimicrob Agents Chemother. Agents Antimicrob baumannii. Acinetobacter 23. 2011;66(10):2298-2307. 2011;66(10):2298-2307. 2007–09. in USA the from non-fermenters and Enterobacteriaceae in mechanisms resistance Perez F, F, Perez J Antimicrob Chemother. Chemother. Antimicrob J 22. Davies TA, Queenan AM, Morrow BJ, et al. Longitudinal survey of carbapenem resistance and and resistance carbapenem of survey Longitudinal al. et BJ, Morrow AM, Queenan TA, Davies 2019. Institute; Standards Laboratory and Clinical PA: Wayne,

23. 2011;66(10):2298-2307. 2011;66(10):2298-2307. 2007–09. in USA the from non-fermenters and Enterobacteriaceae in mechanisms resistance Perez F, F, Perez J Antimicrob Chemother. Chemother. Antimicrob J 22. Davies TA, Queenan AM, Morrow BJ, et al. Longitudinal survey of carbapenem resistance and and resistance carbapenem of survey Longitudinal al. et BJ, Morrow AM, Queenan TA, Davies 2019. Institute; Standards Laboratory and Clinical PA: Wayne,

BAT through Day 49 [34/101 (33.7%) vs 10/49 (20.4%), treatment difference 13.3%, 95% CI (-2.5, 26.9)]. 26.9)]. (-2.5, CI 95% 13.3%, difference treatment (20.4%), 10/49 vs (33.7%) [34/101 49 Day through BAT

22. Davies TA, Queenan AM, Morrow BJ, et al. Longitudinal survey of carbapenem resistance and and resistance carbapenem of survey Longitudinal al. et BJ, Morrow AM, Queenan TA, Davies 2019. Institute; Standards Laboratory and Clinical PA: Wayne, 21. . 29th ed. CLSI supplement M100. M100. supplement CLSI ed. 29th . CLSI. 2020. 28, August Accessed 2019. 20, November Updated Performance Standards for Antimicrobial Susceptibility Testing Susceptibility Antimicrobial for Standards Performance

21. . 29th ed. CLSI supplement M100. M100. supplement CLSI ed. 29th . CLSI. 2020. 28, August Accessed 2019. 20, November Updated Performance Standards for Antimicrobial Susceptibility Testing Susceptibility Antimicrobial for Standards Performance 20. US Food and Drug Administration. Cefiderocol injection. https://www.fda.gov/drugs/development-resources/cefiderocol-injection. https://www.fda.gov/drugs/development-resources/cefiderocol-injection. injection. Cefiderocol Administration. Drug and Food US 2020. 28, August Accessed 19.2)]. All-cause mortality remained higher in patients treated with Fetroja than in patients treated with with treated patients in than Fetroja with treated patients in higher remained mortality All-cause 19.2)]. Subcommittee on Antimicrobial Susceptibility Testing meeting; January 10-12, 2016; Tempe, Arizona. https://clsi.org/meetings/ast/ast-meeting-files-resources/. https://clsi.org/meetings/ast/ast-meeting-files-resources/. Arizona. Tempe, 2016; 10-12, January meeting; Testing Susceptibility Antimicrobial on Subcommittee

20. US Food and Drug Administration. Cefiderocol injection. https://www.fda.gov/drugs/development-resources/cefiderocol-injection. https://www.fda.gov/drugs/development-resources/cefiderocol-injection. injection. Cefiderocol Administration. Drug and Food US 2020. 28, August Accessed Subcommittee on Antimicrobial Susceptibility Testing meeting; January 10-12, 2016; Tempe, Arizona. https://clsi.org/meetings/ast/ast-meeting-files-resources/. https://clsi.org/meetings/ast/ast-meeting-files-resources/. Arizona. Tempe, 2016; 10-12, January meeting; Testing Susceptibility Antimicrobial on Subcommittee 19. Clinical and Laboratory Standards Institute. Summary minutes: minutes: Summary Institute. Standards Laboratory and Clinical 2019;94(4):321-325. . broth. Mueller-Hinton cation-adjusted depleted Diagn Microbiol Infect Dis Infect Microbiol Diagn

in patients treated with BAT [25/101 (24.8%) vs 9/49 (18.4%), treatment difference 6.4%, 95% CI (-8.6, (-8.6, CI 95% 6.4%, difference treatment (18.4%), 9/49 vs (24.8%) [25/101 BAT with treated patients in

Subcommittee on Antimicrobial Susceptibility Testing meeting; January 10-12, 2016; Tempe, Arizona. https://clsi.org/meetings/ast/ast-meeting-files-resources/. https://clsi.org/meetings/ast/ast-meeting-files-resources/. Arizona. Tempe, 2016; 10-12, January meeting; Testing Susceptibility Antimicrobial on Subcommittee 19. Clinical and Laboratory Standards Institute. Summary minutes: minutes: Summary Institute. Standards Laboratory and Clinical 2019;94(4):321-325. . broth. Mueller-Hinton cation-adjusted depleted Diagn Microbiol Infect Dis Infect Microbiol Diagn

19. Clinical and Laboratory Standards Institute. Summary minutes: minutes: Summary Institute. Standards Laboratory and Clinical 2019;94(4):321-325. . broth. Mueller-Hinton cation-adjusted depleted Diagn Microbiol Infect Dis Infect Microbiol Diagn Echols R, Karlowsky JA, Sahm DF. Reproducibility of broth microdilution MICs for the novel siderophore cephalosporin, cefiderocol, determined using iron- using determined cefiderocol, cephalosporin, siderophore novel the for MICs microdilution broth of Reproducibility DF. Sahm JA, Karlowsky R, Echols infections, or sepsis. The 28-Day all-cause mortality was higher in patients treated with Fetroja than than Fetroja with treated patients in higher was mortality all-cause 28-Day The sepsis. or infections, 18. Hackel MA, Tsuji M, Yamano Y, Y, Yamano M, Tsuji MA, Hackel 2016;66(12):5575-5599. nov. fam. and nov., fam. nov., fam. Int J Syst Evol Microbiol. Evol Syst J Int Budviciaceae Morganellaceae Hafniaceae

Echols R, Karlowsky JA, Sahm DF. Reproducibility of broth microdilution MICs for the novel siderophore cephalosporin, cefiderocol, determined using iron- using determined cefiderocol, cephalosporin, siderophore novel the for MICs microdilution broth of Reproducibility DF. Sahm JA, Karlowsky R, Echols 18. Hackel MA, Tsuji M, Yamano Y, Y, Yamano M, Tsuji MA, Hackel 2016;66(12):5575-5599. nov. fam. and nov., fam. nov., fam. Int J Syst Evol Microbiol. Evol Syst J Int Budviciaceae Morganellaceae Hafniaceae fam. nov., nov., fam. nov., fam. nov., fam. , families the into divided nov. ord. for proposal Yersiniaceae Pectobacteriaceae Erwiniaceae Enterobacteriaceae Enterobacterales

The increase in all-cause mortality occurred in patients treated for nosocomial pneumonia, bloodstream bloodstream pneumonia, nosocomial for treated patients in occurred mortality all-cause in increase The

18. Hackel MA, Tsuji M, Yamano Y, Y, Yamano M, Tsuji MA, Hackel 2016;66(12):5575-5599. nov. fam. and nov., fam. nov., fam. Int J Syst Evol Microbiol. Evol Syst J Int Budviciaceae Morganellaceae Hafniaceae fam. nov., nov., fam. nov., fam. nov., fam. , families the into divided nov. ord. for proposal Yersiniaceae Pectobacteriaceae Erwiniaceae Enterobacteriaceae Enterobacterales 17. Adeolu M, Alnajar S, Naushad S, Gupta RS. Genome-based phylogeny and taxonomy of the ‘ the of taxonomy and phylogeny Genome-based RS. Gupta S, Naushad S, Alnajar M, Adeolu doi:10.1186/s13613-015-0061-0. 2015;5(1):61. : : Enterobacteriales’

fam. nov., nov., fam. nov., fam. nov., fam. , families the into divided nov. ord. for proposal Yersiniaceae Pectobacteriaceae Erwiniaceae Enterobacteriaceae Enterobacterales 17. Adeolu M, Alnajar S, Naushad S, Gupta RS. Genome-based phylogeny and taxonomy of the ‘ the of taxonomy and phylogeny Genome-based RS. Gupta S, Naushad S, Alnajar M, Adeolu doi:10.1186/s13613-015-0061-0. 2015;5(1):61. : : Enterobacteriales’

16. . . bacilli. Gram-negative in resistance antimicrobial of Mechanisms F. Barbier PL, Woerther É, Ruppé 2012;25(1):2-41. . Ann Intensive Care Intensive Ann Rev Microbiol Clin

Bacterial Infections (continued) Infections Bacterial

17. Adeolu M, Alnajar S, Naushad S, Gupta RS. Genome-based phylogeny and taxonomy of the ‘ the of taxonomy and phylogeny Genome-based RS. Gupta S, Naushad S, Alnajar M, Adeolu doi:10.1186/s13613-015-0061-0. 2015;5(1):61. : : Enterobacteriales’ 16. . . bacilli. Gram-negative in resistance antimicrobial of Mechanisms F. Barbier PL, Woerther É, Ruppé 2012;25(1):2-41. . Ann Intensive Care Intensive Ann Rev Microbiol Clin

16. . . bacilli. Gram-negative in resistance antimicrobial of Mechanisms F. Barbier PL, Woerther É, Ruppé 2012;25(1):2-41. . Ann Intensive Care Intensive Ann Rev Microbiol Clin 15. 14. : an emerging global opportunistic pathogen. pathogen. opportunistic global emerging an : JS. Brooke file. on Data doi:10.1128/AAC.01076-18. 2018;62(10):e01076-18. Stenotrophomonas maltophilia Stenotrophomonas Increase in All-Cause Mortality in Patients with Carbapenem-Resistant Gram-Negative Gram-Negative Carbapenem-Resistant with Patients in Mortality All-Cause in Increase 13. . . ϐ-lactamases. on perspectives present and Past K. Bush 2007;20(3):440-458. . ϐ-lactamases. versatile Antimicrob Agents Chemother Agents Antimicrob Rev Microbiol Clin

. . ϐ-lactamases. on perspectives present and Past K. Bush 2007;20(3):440-458. . ϐ-lactamases. versatile Antimicrob Agents Chemother Agents Antimicrob Rev Microbiol Clin

(continued) (continued) PRECAUTIONS AND WARNINGS

13. . . ϐ-lactamases. on perspectives present and Past K. Bush 2007;20(3):440-458. . ϐ-lactamases. versatile Antimicrob Agents Chemother Agents Antimicrob Rev Microbiol Clin 12. Queenan AM, Bush K. Carbapenemases: the the Carbapenemases: K. Bush AM, Queenan 2020;26(7):S1-S3. City. York New in centers medical to endemic Microb Drug Resist. Drug Microb baumannii Acinetobacter

11. , and and , , against cefiderocol of Activity J. Quale D, Landman Z, Khan A, Iregui 2020;26(7):1-5. . Pseudomonas aeruginosa Pseudomonas Enterobacterales Resist Drug Microb

12. Queenan AM, Bush K. Carbapenemases: the the Carbapenemases: K. Bush AM, Queenan 2020;26(7):S1-S3. City. York New in centers medical to endemic Microb Drug Resist. Drug Microb baumannii Acinetobacter 11. , and and , , against cefiderocol of Activity J. Quale D, Landman Z, Khan A, Iregui 2020;26(7):1-5. . Pseudomonas aeruginosa Pseudomonas Enterobacterales Resist Drug Microb

IMPORTANT SAFETY INFORMATION (continued) (continued) INFORMATION SAFETY IMPORTANT

11. , and and , , against cefiderocol of Activity J. Quale D, Landman Z, Khan A, Iregui 2020;26(7):1-5. . Pseudomonas aeruginosa Pseudomonas Enterobacterales Resist Drug Microb endemic to medical centers in New York City. City. York New in centers medical to endemic and , , against cefiderocol of Activity J. Quale Acinetobacter baumannii Acinetobacter aeruginosa Pseudomonas Enterobacterales 10. Iregui A, Khan Z, Landman D, D, Landman Z, Khan A, Iregui doi:10.1128/AAC.01454-17. 2018;62(1). . bacteria. Gram-negative against cephalosporin, Antimicrob Agents Chemother Agents Antimicrob

endemic to medical centers in New York City. City. York New in centers medical to endemic and , , against cefiderocol of Activity J. Quale Acinetobacter baumannii Acinetobacter aeruginosa Pseudomonas Enterobacterales 10. Iregui A, Khan Z, Landman D, D, Landman Z, Khan A, Iregui doi:10.1128/AAC.01454-17. 2018;62(1). . bacteria. Gram-negative against cephalosporin, Antimicrob Agents Chemother Agents Antimicrob 9. antibacterial properties of cefiderocol, a novel siderophore siderophore novel a cefiderocol, of properties antibacterial al. et M, Ota T, Sato A, Ito doi:10.1128/mBio.01541-16. 2016;7(5):e01541-16. . In vitro In mBio

10. Iregui A, Khan Z, Landman D, D, Landman Z, Khan A, Iregui doi:10.1128/AAC.01454-17. 2018;62(1). . bacteria. Gram-negative against cephalosporin, Antimicrob Agents Chemother Agents Antimicrob 9. antibacterial properties of cefiderocol, a novel siderophore siderophore novel a cefiderocol, of properties antibacterial al. et M, Ota T, Sato A, Ito doi:10.1128/mBio.01541-16. 2016;7(5):e01541-16. . In vitro In mBio 8. Miller SI. Antibiotic resistance and regulation of the Gram-negative bacterial outer membrane barrier by host innate immune molecules. molecules. immune innate host by barrier membrane outer bacterial Gram-negative the of regulation and resistance Antibiotic SI. Miller 7396-7401.

9. antibacterial properties of cefiderocol, a novel siderophore siderophore novel a cefiderocol, of properties antibacterial al. et M, Ota T, Sato A, Ito doi:10.1128/mBio.01541-16. 2016;7(5):e01541-16. . In vitro In mBio 8. Miller SI. Antibiotic resistance and regulation of the Gram-negative bacterial outer membrane barrier by host innate immune molecules. molecules. immune innate host by barrier membrane outer bacterial Gram-negative the of regulation and resistance Antibiotic SI. Miller 7396-7401.

. 2016;60(12): . . against activity antibacterial for systems transporter iron ferric utilizes cefiderocol Antimicrob Agents Chemother Agents Antimicrob aeruginosa Pseudomonas

• Fetroja is active against isolates that are resistant due to efflux pump up-regulation pump efflux to due resistant are that isolates against active is Fetroja • 7. Ito A, Nishikawa T, Matsumoto S, et al. Siderophore cephalosporin cephalosporin Siderophore al. et S, Matsumoto T, Nishikawa A, Ito 7):S538-S543. 2019;69(suppl . cephalosporin. siderophore novel a of profiles Clin Infect Dis Infect Clin

1,9-11

. 2016;60(12): . . against activity antibacterial for systems transporter iron ferric utilizes cefiderocol Antimicrob Agents Chemother Agents Antimicrob aeruginosa Pseudomonas 7. Ito A, Nishikawa T, Matsumoto S, et al. Siderophore cephalosporin cephalosporin Siderophore al. et S, Matsumoto T, Nishikawa A, Ito 7):S538-S543. 2019;69(suppl . cephalosporin. siderophore novel a of profiles Clin Infect Dis Infect Clin 6. Sato T, Yamawaki K. Cefiderocol: Discovery, chemistry, and in vivo vivo in and chemistry, Discovery, Cefiderocol: K. Yamawaki T, Sato 2018;155:847-868. . relationship. activity Structure bacteria: resistant drug Eur J Med Chem Med J Eur

7. Ito A, Nishikawa T, Matsumoto S, et al. Siderophore cephalosporin cephalosporin Siderophore al. et S, Matsumoto T, Nishikawa A, Ito 7):S538-S543. 2019;69(suppl . cephalosporin. siderophore novel a of profiles Clin Infect Dis Infect Clin 6. Sato T, Yamawaki K. Cefiderocol: Discovery, chemistry, and in vivo vivo in and chemistry, Discovery, Cefiderocol: K. Yamawaki T, Sato 2018;155:847-868. . relationship. activity Structure bacteria: resistant drug Eur J Med Chem Med J Eur and other Gram-negative pathogens including multi- including pathogens Gram-negative other and against activities potent exhibiting cephalosporin siderophore new A (S-649266), Pseudomonas aeruginosa Pseudomonas

6. transport system transport Sato T, Yamawaki K. Cefiderocol: Discovery, chemistry, and in vivo vivo in and chemistry, Discovery, Cefiderocol: K. Yamawaki T, Sato 2018;155:847-868. . relationship. activity Structure bacteria: resistant drug Eur J Med Chem Med J Eur and other Gram-negative pathogens including multi- including pathogens Gram-negative other and against activities potent exhibiting cephalosporin siderophore new A (S-649266), Pseudomonas aeruginosa Pseudomonas 5. Aoki T, Yoshizawa H, Yamawaki K, et al. Cefiderocol Cefiderocol al. et K, Yamawaki H, Yoshizawa T, Aoki 2019;79(3):271-289. . bacilli. Gram-negative multidrug-resistant and carbapenem-resistant Drugs

1,4,9

and other Gram-negative pathogens including multi- including pathogens Gram-negative other and against activities potent exhibiting cephalosporin siderophore new A (S-649266), Pseudomonas aeruginosa Pseudomonas 5. Aoki T, Yoshizawa H, Yamawaki K, et al. Cefiderocol Cefiderocol al. et K, Yamawaki H, Yoshizawa T, Aoki 2019;79(3):271-289. . bacilli. Gram-negative multidrug-resistant and carbapenem-resistant Drugs

• Fetroja is able to overcome porin channel changes as it also enters through the active iron iron active the through enters also it as changes channel porin overcome to able is Fetroja •

5. Aoki T, Yoshizawa H, Yamawaki K, et al. Cefiderocol Cefiderocol al. et K, Yamawaki H, Yoshizawa T, Aoki 2019;79(3):271-289. . bacilli. Gram-negative multidrug-resistant and carbapenem-resistant Drugs 4. Zhanel GG, Golden AR, Zelenistky S, et al. Cefiderocol: a siderophore cephalosporin with activity against against activity with cephalosporin siderophore a Cefiderocol: al. et S, Zelenistky AR, Golden GG, Zhanel 2009;15(17):1956-1973. . modulator. Curr Pharm Des Pharm Curr 3. Actor JK, Hwang SA, Kruzel ML. Lactoferrin as a natural immune immune natural a as Lactoferrin ML. Kruzel SA, Hwang JK, Actor 2017;105:68-78. . interactions. host-bacterial of modulation and Free Radic Biol Med Biol Radic Free

4. Zhanel GG, Golden AR, Zelenistky S, et al. Cefiderocol: a siderophore cephalosporin with activity against against activity with cephalosporin siderophore a Cefiderocol: al. et S, Zelenistky AR, Golden GG, Zhanel 2009;15(17):1956-1973. . modulator. Curr Pharm Des Pharm Curr 3. Actor JK, Hwang SA, Kruzel ML. Lactoferrin as a natural immune immune natural a as Lactoferrin ML. Kruzel SA, Hwang JK, Actor 2017;105:68-78. . interactions. host-bacterial of modulation and Free Radic Biol Med Biol Radic Free

3. Actor JK, Hwang SA, Kruzel ML. Lactoferrin as a natural immune immune natural a as Lactoferrin ML. Kruzel SA, Hwang JK, Actor 2017;105:68-78. . interactions. host-bacterial of modulation and Free Radic Biol Med Biol Radic Free 2. 1. References: Ellermann M, Arthur JC. Siderophore-mediated iron acquisition acquisition iron Siderophore-mediated JC. Arthur M, Ellermann 2020. Inc.; Shionogi NJ: Park, Florham insert]. [package (cefiderocol) Fetroja

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Fe Fe hostlactoferrin cells produce to sequester iron-binding iron Fe Iron transported into the cell • Visit www.thermofisher.com/AST™ or email your local representative at LEARN MORE AT Plates including cefiderocol (MIC range: 0.03–32Photograph µg/mL): used courtesy of Thermo Fisher limit drug access 2 Inlactoferrin response to to sequester infection, iron to allow growth Sensititre MIC Plates Scientific; copying prohibited. Fe [email protected] including cefiderocol to(MIC order range: 0.03–32 µg/mL): host cells produce iron-binding Fe • Visit www.thermofisher.com/AST or email your local representative at LEARNFetroja.com MORE AT INNER MEMBRANE Fe lactoferrin to sequester iron Exact mechanisms • VisitCatalog www.thermofisher.com/AST numbers: MDRGN2F, MDRGNX2F or email (withyour localcolistin)–10 representative plates/box at LEARN MORE AT [email protected] including cefiderocol to(MIC order range: 0.03–32 µg/mL): Fetroja.com Fe and transporters [email protected] to order Lactoferrin Exactmay vary mechanisms across • Catalog numbers: MDRGN2F, MDRGNX2F (with colistin)–10Adap tplates/boxed from Zhanel et al. IMPORTANT SAFETY INFORMATION (continued) Fetroja.com •Standard VisitPENICILLINBINDING www.thermofisher.com/AST Sensititre PROTEINS Mueller-Hinton broth or isemail used yourfor inoculation local representative at LEARN MORE AT Bacterial siderophoreFe Exactandpathogens transporters mechanisms • Catalog numbers: MDRGN2F, MDRGNX2F (with colistin)–10 plates/box Lactoferrin [email protected] to order WARNINGS AND PRECAUTIONS (continued) Fe andmay transporters vary across Standard Sensititre Mueller-Hinton broth is used for inoculation IMPORTANT SAFETY INFORMATION (continued) Fetroja.com INDICATIONS Lactoferrin Bacterial siderophore • The unique structure of Fetroja allows it to remain stable against all classes of ϐ-lactamases1,5 IMPORTANTDevelopment of SAFETY Drug-Resistant INFORMATION Bacteria (continued) Exactmaypathogens vary mechanisms across Standard• Catalog Sensititre numbers: Mueller-Hinton MDRGN2F, MDRGNX2F broth is used (with for inoculation colistin)–10 plates/box WARNINGS AND PRECAUTIONS (continued) Fetroja® (cefiderocol) is indicated in patients 18 years of age or olderBacterial for siderophore the treatment of complicatedpathogens Prescribing Fetroja in the absence of a proven or strongly suspected bacterial infection or a prophylactic INDICATIONS Fe and transporters DevelopmentWARNINGS AND of Drug-Resistant PRECAUTIONS Bacteria(continued) urinary tract infections (cUTIs), includingLactoferrin pyelonephritis caused by the following susceptible mayGram-negative vary across • Fetroja is able to overcome porin channel changes as it also enters through the active iron IMPORTANT SAFETY INFORMATION (continued) INDICATIONS® StandardUSFET-0306 02/21 Sensititre Mueller-Hinton broth is used for inoculation Developmentindication is unlikely of Drug-Resistant to provide benefit Bacteria to the patient and increases the risk of the development of drug- Fetroja (cefiderocol) is indicated in patients 18 years of age or olderBacterial for siderophore the treatment of complicatedpathogens Prescribing Fetroja in the absence of a proven or strongly suspected bacterial infection or a prophylactic microorganisms:® Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and transport system1,4,9 WARNINGSresistant bacteria. AND PRECAUTIONS (continued) urinaryFetroja tract(cefiderocol) infections is (cUTIs),indicated including in patients pyelonephritis 18 years of agecaused or older by the for following the treatment susceptible of complicated Gram-negative USFET-0306USFET-0307 02/21 indicationPrescribing is Fetrojaunlikely in to the provide absence benefit of a toproven the patient or strongly and increases suspected the bacterial risk of theinfection development or a prophylactic of drug- INDICATIONSEnterobacter cloacae complex. DevelopmentADVERSE REACTIONS of Drug-Resistant Bacteria microorganisms:urinary tract infections Escherichia (cUTIs), coli including, Klebsiella pyelonephritis pneumoniae ,caused Proteus by mirabilis the following, Pseudomonas susceptible aeruginosa Gram-negative, and • FetrojaUSFET-0306 is active 02/21 against isolates that are resistant due to efflux pump up-regulation1,9-11 resistantindication bacteria. is unlikely to provide benefit to the patient and increases the risk of the development of drug- microorganisms:Fetroja® is (cefiderocol) indicated Escherichia in is patients indicated coli 18, inKlebsiella years patients of pneumoniaeage 18 years or older of ,age Proteusfor orthe older treatmentmirabilis for the, Pseudomonas oftreatment hospital-acquired of aeruginosacomplicated bacterial, and PrescribingThe most common Fetroja adverse in the absence reactions of aoccurring proven or in strongly (≥2%) of suspected patients receiving bacterial Fetroja infection compared or a prophylactic to imipenem/ Enterobacter cloacae complex. Laboratory Specialists, Inc. (LSI) ADVERSEresistant bacteria. REACTIONS urinaryEnterobacterpneumonia tract and cloacaeinfections ventilator-associated complex. (cUTIs), including bacterial pyelonephritis pneumonia, caused caused by the byfollowing the following susceptible susceptible Gram-negative Gram- USFET-0306 02/21 indicationcilastatin in is the unlikely cUTI trialto provide were: benefitdiarrhea to (4% the vspatient 6%), infusionand increases site reactions the risk (4% of the vs development5%), constipation of drug- (3% Fetroja is indicated in patients 18 years of age or older for the treatment of hospital-acquired bacterial TheADVERSE most common REACTIONS adverse reactions occurring in (≥2%) of patients receiving Fetroja compared to imipenem/ microorganisms:negative microorganisms: Escherichia Acinetobacter coli, Klebsiella baumannii pneumoniae complex,, Proteus Escherichia mirabilis, Pseudomonas coli, Enterobacter aeruginosa cloacae, and IMPORTANTLaboratoryPanel SAFETY of Isolates INFORMATION Specialists, (continued) Inc. (LSI) resistantvs 4%), rash bacteria. (3% vs <1%), candidiasis (2% vs 3%), cough (2% vs <1%), elevations in liver tests (2% vs <1%), pneumoniaFetrojacomplex, is Klebsiellaindicated and ventilator-associated pneumoniaein patients 18, Pseudomonas years bacterial of age oraeruginosa pneumonia, older for, theand caused treatment Serratia by the marcescens of following hospital-acquired. susceptible bacterial Gram- Laboratory Specialists, Inc. (LSI) cilastatinThe most incommon the cUTI adverse trial were: reactions diarrhea occurring (4% vs 6%),in (≥ 2%)infusion of patients site reactions receiving (4% Fetroja vs 5%), compared constipation to imipenem/ (3% pneumoniaEnterobacter and cloacae ventilator-associated complex. bacterial pneumonia, caused by the following susceptible Gram- ADVERSEheadache (2%REACTIONS vs 5%), hypokalemia (2% vs 3%), nausea (2% vs 4%), and vomiting (2% vs 1%). The most negative microorganisms: Acinetobacter baumannii complex, Escherichia coli, Enterobacter cloacae WARNINGSPanel AND PRECAUTIONS of Isolates (continued) vscilastatin 4%), rash in the (3% cUTI vs <1%), trial were:candidiasis diarrhea (2% (4% vs 3%), vs 6%), cough infusion (2% vs site <1%), reactions elevations (4% vsin liver5%), testsconstipation (2% vs <1%),(3% negativeFetrojaUSAGE is microorganisms: indicated in patients Acinetobacter 18 years of baumannii age or older complex, for the Escherichia treatment ofcoli hospital-acquired, Enterobacter cloacae bacterial Thecommon most adversecommon reactions adverse occurringreactions occurringin (≥4%) of in patients ( 2%) of receiving patients Fetrojareceiving compared Fetroja compared to meropenem to imipenem/ in the complex, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens. IncreaseLaboratoryPanel •in Visit All-Cause www.labspec.org, of Mortality Isolates Specialists, in Patients email with your Carbapenem-ResistantInc. local (LSI) representative Gram-Negative at [email protected], headachevs 4%), rash (2% (3% vs vs5%), <1%), hypokalemia candidiasis (2% (2% vs vs 3%), 3%), nausea cough≥ (2% (2% vs vs 4%), <1%), and elevations vomiting in (2% liver vs tests 1%). (2%The vsmost <1%), pneumoniacomplex,To reduce Klebsiella the and development ventilator-associated pneumoniae of drug-resistant, Pseudomonas bacterial bacteria aeruginosa pneumonia, and, maintainand caused Serratia bythe the marcescenseffectiveness following. susceptible of Fetroja andGram- cilastatinHABP/VABP in the trial cUTI were: trial elevations were: diarrhea in liver (4% tests vs (16% 6%), vsinfusion 16%), sitehypokalemia reactions (11% (4% vs vs 5%), 15%), constipation diarrhea (9% (3% vs 9%), USAGE Bacterial• Infections orVisit call www.labspec.org, (440) (continued) 835-4458 to email order your local representative at [email protected], commonheadachehypomagnesemia adverse (2% vs 5%), reactions (5% hypokalemia vs <1%), occurring and (2%atrial in vs(≥ fibrillation 4%)3%), of nausea patients (5% (2% vs receiving 3%).vs 4%), andFetroja vomiting compared (2% vs to 1%).meropenem The most in the negativeother antibacterial microorganisms: drugs, FetrojaAcinetobacter should baumannii be used only complex, to treat Escherichia or prevent coliinfections, Enterobacter that are cloacae proven or HABP/VABPcommonvs 4%), rash adverse (3%trial vs were:reactions <1%), elevations candidiasis occurring in liver (2%in (≥ testsvs4%) 3%), of(16% patientscough vs 16%), (2% receiving vs hypokalemia <1%), Fetroja elevations (11%compared invs liver 15%), to tests meropenem diarrhea (2% vs (9% <1%), in vs the 9%), ToUSAGE reduce the development of drug-resistant bacteria and maintain the effectiveness of Fetroja and The increasePanel• Visit in all-cause www.labspec.org, of Isolates mortality occurred email in your patients local treated representative for nosocomial at pneumonia,[email protected], bloodstream complex,strongly suspected Klebsiella pneumoniaeto be caused, Pseudomonasby susceptible aeruginosa bacteria. , and Serratia marcescens. or call (440) 835-4458 to order hypomagnesemiaHABP/VABPheadacheCONTRAINDICATIONS (2% trial vs 5%),were: (5% hypokalemia vs elevations <1%), and in (2%atrial liver vs testsfibrillation 3%), (16%nausea (5%vs 16%),(2% vs 3%).vs hypokalemia 4%), and vomiting (11% vs(2% 15%), vs 1%). diarrhea The most (9% vs 9%), otherTo reduce antibacterial the development drugs, Fetroja of drug-resistant should be used bacteria only andto treat maintain or prevent the effectiveness infections that of Fetrojaare proven and or infections, or sepsis.call (440) The 28-Day835-4458 all-cause to order mortality was higher in patients treated with Fetroja than commonFetroja is adversecontraindicated reactions in occurring patients with in ( a4%) known of patients history receivingof severe Fetrojahypersensitivity compared to to cefiderocol meropenem or otherin the stronglyotherUSAGE antibacterial suspected drugs,to be caused Fetroja by should susceptible be used bacteria. only to treat or prevent infections that are proven or •Shionogi Visit www.labspec.org, has collaborated with email LSI your to develop local arepresentative panel of isolates at for [email protected], laboratories to CONTRAINDICATIONShypomagnesemia (5% vs <1%), and atrial≥ fibrillation (5% vs 3%). IMPORTANT SAFETY INFORMATION in patients treated with BAT [25/101 (24.8%) vs 9/49 (18.4%), treatment difference 6.4%, 95% CI (-8.6, HABP/VABPbeta-lactam trialantibacterial were: elevations drugs, or in any liver other tests component (16% vs 16%), of Fetroja. hypokalemia (11% vs 15%), diarrhea (9% vs 9%), stronglyTo reduce suspected the development to be caused of drug-resistant by susceptible bacteria bacteria. and maintain the effectiveness of Fetroja and perform verification and validation FetrojaCONTRAINDICATIONS is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or other CONTRAINDICATIONS 19.2)]. All-causeShionogior call mortality has(440) collaborated 835-4458 remained higher towith order LSI in patients to develop treated a panel with ofFetroja isolates than for in laboratoriespatients treated to with hypomagnesemia (5% vs <1%), and atrial fibrillation (5% vs 3%). otherIMPORTANT antibacterial SAFETY drugs, INFORMATIONFetroja should be used only to treat or prevent infections that are proven or BAT throughperformShionogi Day 49 verificationhas [34/101 collaborated (33.7%) and validationvs with 10/49 LSI (20.4%), to develop treatment a panel difference of isolates 13.3%, for 95%laboratories CI (-2.5, 26.9)]. to beta-lactamFetrojaPlease issee contraindicated additional antibacterial Important indrugs, patients or Safety any with other Information a known component history throughout ofof Fetroja.severe and hypersensitivity enclosed Full to Prescribing cefiderocol or other stronglyIMPORTANTFetroja is suspected contraindicated SAFETY to be caused INFORMATIONin patients by susceptible with a known bacteria. history of severe hypersensitivity to cefiderocol or beta-lactamCONTRAINDICATIONSInformation antibacterialfor Fetroja in drugs, pocket. or any other component of Fetroja. CONTRAINDICATIONSother beta-lactam antibacterial drugs, or any other component of Fetroja. Generally,perform deaths were verification in patients and with validation infections caused by Gram-negative organisms, including non- Please see additional Important Safety Information throughout and enclosed Full Prescribing FetrojaCONTRAINDICATIONS is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or fermentersShionogi such as has Acinetobacter collaborated baumannii with LSI complex, to develop Stenotrophomonas a panel of isolates maltophilia for laboratories, and Pseudomonas to Fetroja is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or other IMPORTANT SAFETY INFORMATION PleaseInformation see additional for Fetroja Important in pocket. Safety Information throughout and enclosed Full Prescribing otherFetrojaPlease beta-lactam seeis contraindicated additional antibacterial Important in patients drugs, Safety with or Information anya known other history component throughout of severe of and Fetroja. hypersensitivity enclosed Full toPrescribing cefiderocol or aeruginosa, and were the result of worsening or complications of infection, or underlying comorbidities. beta-lactam antibacterial ©drugs, 2021 Shionogi or any Inc. Florham other Park, component NJ 07932. All Rights of Fetroja. Reserved. Fetroja is a registered trademark of Shionogi & Co., Ltd. Osaka, Japan. perform verification and validation Information for Fetroja inAll pocket. other trademarks are the property of their respective owners. USFET-0306 02/21 otherCONTRAINDICATIONSInformation beta-lactam for Fetroja antibacterial in pocket. drugs, or any other component of Fetroja. The cause of the increase in mortality has not been established. Please see additional Important Safety Information throughout and enclosed Full Prescribing USFET-0307USFET-0306 02/21 Please see additional Important© 2021 Shionogi Safety Inc. Florham Information Park, NJ 07932. throughout All Rights Reserved. and Fetroja enclosedis a registered Fulltrademark Prescribing of Shionogi & Co., Ltd. Osaka, Japan. Fetroja is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or All other trademarks are the property of their respective owners. USFET-0306 02/21 InformationPlease see additional for Fetroja Important in pocket. Safety Information throughout and enclosed Full Prescribing

CloselyPlease seemonitor additional the clinical Important response Safety to therapyInformation in patients throughout with cUTI and andFull HABP/VABP. Prescribing Information Information for Fetroja in© pocket. 2021 Shionogi Inc. Florham Park, NJ 07932. All Rights Reserved. Fetroja is a registered trademark of Shionogi & Co., Ltd. Osaka, Japan. other beta-lactam antibacterial drugs, or any other component of Fetroja.

USFET-0306 02/21 All other trademarks are the property of their respective owners. USFET-0306 02/21 Information for Fetroja in pocket.

for Fetroja located at the end. 3 8 7 Please see additional Important Safety Information throughout and enclosed Full Prescribing

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All other trademarks are the property of Agents. their respectiveAntimicrob J owners.Int USFET-0306 02/21

2019;53(2):177-184. Study). (SIDERO-WT-2014 isolates metallo-ϐ-lactamase-producing USFET-0306 02/21 Agents. Antimicrob J Int

7 25. Fernández L, Hancock REW. Adaptive and mutational resistance: role of porins and efflux efflux and porins of role resistance: mutational and Adaptive REW. Hancock L, Fernández 2009;53(11):4783-4788. . . Antimicrob Agents Chemother Agents Antimicrob aeruginosa

2019;53(2):177-184. Study). (SIDERO-WT-2014 isolates metallo-ϐ-lactamase-producing Int J Antimicrob Agents. Agents. Antimicrob J Int 24. Rodríguez-Martínez JM, Poirel L, Nordmann P. Molecular epidemiology and mechanisms of carbapenem resistance in in resistance carbapenem of mechanisms and epidemiology Molecular P. Nordmann L, Poirel JM, Rodríguez-Martínez 2007;51(10):3471-3484. Pseudomonas Pseudomonas

7 26. Kazmierczak KM, Tsuji M, Wise MG, et al. In vitro activity of cefiderocol, a siderophore siderophore a cefiderocol, of activity vitro In al. et MG, Wise M, Tsuji KM, Kazmierczak 2012;25(4):661-681. . resistance. drug in pumps Clin Microbiol Rev Microbiol Clin 23. Perez F, F, Perez 2011;66(10):2298-2307. 2007–09. in USA the from non-fermenters and Enterobacteriaceae in mechanisms resistance J Antimicrob Chemother. Chemother. Antimicrob J

2019;53(2):177-184. Study). (SIDERO-WT-2014 isolates metallo-ϐ-lactamase-producing Int J Antimicrob Agents. Agents. Antimicrob J Int 25. Fernández L, Hancock REW. Adaptive and mutational resistance: role of porins and efflux efflux and porins of role resistance: mutational and Adaptive REW. Hancock L, Fernández 2009;53(11):4783-4788. . . Antimicrob Agents Chemother Agents Antimicrob aeruginosa 22. Davies TA, Queenan AM, Morrow BJ, et al. Longitudinal survey of carbapenem resistance and and resistance carbapenem of survey Longitudinal al. et BJ, Morrow AM, Queenan TA, Davies 2019. Institute; Standards Laboratory and Clinical PA: Wayne,

multidrug-resistant of challenge Global RA. Bonomo PN, Rather BK, Becker KM, Hujer AM, Hujer Antimicrob Agents Chemother. Agents Antimicrob baumannii. Acinetobacter

cephalosporin, against a recent collection of clinically relevant carbapenem-non-susceptible Gram-negative bacilli, including serine carbapenemase- and and carbapenemase- serine including bacilli, Gram-negative carbapenem-non-susceptible relevant clinically of collection recent a against cephalosporin, 24. Rodríguez-Martínez JM, Poirel L, Nordmann P. Molecular epidemiology and mechanisms of carbapenem resistance in in resistance carbapenem of mechanisms and epidemiology Molecular P. Nordmann L, Poirel JM, Rodríguez-Martínez 2007;51(10):3471-3484. Pseudomonas Pseudomonas 21. . 29th ed. CLSI supplement M100. M100. supplement CLSI ed. 29th . CLSI. 2020. 28, August Accessed 2019. 20, November Updated Performance Standards for Antimicrobial Susceptibility Testing Susceptibility Antimicrobial for Standards Performance

23. Perez F, F, Perez 2011;66(10):2298-2307. 2007–09. in USA the from non-fermenters and Enterobacteriaceae in mechanisms resistance J Antimicrob Chemother. Chemother. Antimicrob J

26. Kazmierczak KM, Tsuji M, Wise MG, et al. In vitro activity of cefiderocol, a siderophore siderophore a cefiderocol, of activity vitro In al. et MG, Wise M, Tsuji KM, Kazmierczak 2012;25(4):661-681. . resistance. drug in pumps Clin Microbiol Rev Microbiol Clin multidrug-resistant of challenge Global RA. Bonomo PN, Rather BK, Becker KM, Hujer AM, Hujer Antimicrob Agents Chemother. Agents Antimicrob baumannii. Acinetobacter 20. US Food and Drug Administration. Cefiderocol injection. https://www.fda.gov/drugs/development-resources/cefiderocol-injection. https://www.fda.gov/drugs/development-resources/cefiderocol-injection. injection. Cefiderocol Administration. Drug and Food US 2020. 28, August Accessed

25. Fernández L, Hancock REW. Adaptive and mutational resistance: role of porins and efflux efflux and porins of role resistance: mutational and Adaptive REW. Hancock L, Fernández 2009;53(11):4783-4788. . . Antimicrob Agents Chemother Agents Antimicrob aeruginosa 23. Perez F, F, Perez 2011;66(10):2298-2307. 2007–09. in USA the from non-fermenters and Enterobacteriaceae in mechanisms resistance J Antimicrob Chemother. Chemother. Antimicrob J Subcommittee on Antimicrobial Susceptibility Testing meeting; January 10-12, 2016; Tempe, Arizona. https://clsi.org/meetings/ast/ast-meeting-files-resources/. https://clsi.org/meetings/ast/ast-meeting-files-resources/. Arizona. Tempe, 2016; 10-12, January meeting; Testing Susceptibility Antimicrobial on Subcommittee

24. Rodríguez-Martínez JM, Poirel L, Nordmann P. Molecular epidemiology and mechanisms of carbapenem resistance in in resistance carbapenem of mechanisms and epidemiology Molecular P. Nordmann L, Poirel JM, Rodríguez-Martínez 2007;51(10):3471-3484. Pseudomonas Pseudomonas 22. Davies TA, Queenan AM, Morrow BJ, et al. Longitudinal survey of carbapenem resistance and and resistance carbapenem of survey Longitudinal al. et BJ, Morrow AM, Queenan TA, Davies 2019. Institute; Standards Laboratory and Clinical PA: Wayne, 19. Clinical and Laboratory Standards Institute. Summary minutes: minutes: Summary Institute. Standards Laboratory and Clinical 2019;94(4):321-325. . broth. Mueller-Hinton cation-adjusted depleted Diagn Microbiol Infect Dis Infect Microbiol Diagn

multidrug-resistant of challenge Global RA. Bonomo PN, Rather BK, Becker KM, Hujer AM, Hujer Antimicrob Agents Chemother. Agents Antimicrob baumannii. Acinetobacter 21. . 29th ed. CLSI supplement M100. M100. supplement CLSI ed. 29th . CLSI. 2020. 28, August Accessed 2019. 20, November Updated Performance Standards for Antimicrobial Susceptibility Testing Susceptibility Antimicrobial for Standards Performance Echols R, Karlowsky JA, Sahm DF. Reproducibility of broth microdilution MICs for the novel siderophore cephalosporin, cefiderocol, determined using iron- using determined cefiderocol, cephalosporin, siderophore novel the for MICs microdilution broth of Reproducibility DF. Sahm JA, Karlowsky R, Echols

23. Perez F, F, Perez 2011;66(10):2298-2307. 2007–09. in USA the from non-fermenters and Enterobacteriaceae in mechanisms resistance J Antimicrob Chemother. Chemother. Antimicrob J 20. US Food and Drug Administration. Cefiderocol injection. https://www.fda.gov/drugs/development-resources/cefiderocol-injection. https://www.fda.gov/drugs/development-resources/cefiderocol-injection. injection. Cefiderocol Administration. Drug and Food US 2020. 28, August Accessed 18. Hackel MA, Tsuji M, Yamano Y, Y, Yamano M, Tsuji MA, Hackel 2016;66(12):5575-5599. nov. fam. and nov., fam. nov., fam. Int J Syst Evol Microbiol. Evol Syst J Int Budviciaceae Morganellaceae Hafniaceae

22. Davies TA, Queenan AM, Morrow BJ, et al. Longitudinal survey of carbapenem resistance and and resistance carbapenem of survey Longitudinal al. et BJ, Morrow AM, Queenan TA, Davies 2019. Institute; Standards Laboratory and Clinical PA: Wayne, Subcommittee on Antimicrobial Susceptibility Testing meeting; January 10-12, 2016; Tempe, Arizona. https://clsi.org/meetings/ast/ast-meeting-files-resources/. https://clsi.org/meetings/ast/ast-meeting-files-resources/. Arizona. Tempe, 2016; 10-12, January meeting; Testing Susceptibility Antimicrobial on Subcommittee fam. nov., nov., fam. nov., fam. nov., fam. , families the into divided nov. ord. for proposal Yersiniaceae Pectobacteriaceae Erwiniaceae Enterobacteriaceae Enterobacterales

21. . 29th ed. CLSI supplement M100. M100. supplement CLSI ed. 29th . CLSI. 2020. 28, August Accessed 2019. 20, November Updated Performance Standards for Antimicrobial Susceptibility Testing Susceptibility Antimicrobial for Standards Performance 19. Clinical and Laboratory Standards Institute. Summary minutes: minutes: Summary Institute. Standards Laboratory and Clinical 2019;94(4):321-325. . broth. Mueller-Hinton cation-adjusted depleted Diagn Microbiol Infect Dis Infect Microbiol Diagn 17. : : ‘ the of taxonomy and phylogeny Genome-based RS. Gupta S, Naushad S, Alnajar M, Adeolu doi:10.1186/s13613-015-0061-0. 2015;5(1):61. Enterobacteriales’

20. US Food and Drug Administration. Cefiderocol injection. https://www.fda.gov/drugs/development-resources/cefiderocol-injection. https://www.fda.gov/drugs/development-resources/cefiderocol-injection. injection. Cefiderocol Administration. Drug and Food US 2020. 28, August Accessed Echols R, Karlowsky JA, Sahm DF. Reproducibility of broth microdilution MICs for the novel siderophore cephalosporin, cefiderocol, determined using iron- using determined cefiderocol, cephalosporin, siderophore novel the for MICs microdilution broth of Reproducibility DF. Sahm JA, Karlowsky R, Echols 16. . . bacilli. Gram-negative in resistance antimicrobial of Mechanisms F. Barbier PL, Woerther É, Ruppé 2012;25(1):2-41. . Ann Intensive Care Intensive Ann Rev Microbiol Clin

fam. nov., nov., fam. nov., fam. nov., fam. , families the into divided nov. ord. for proposal Yersiniaceae Pectobacteriaceae Erwiniaceae Enterobacteriaceae Enterobacterales

Subcommittee on Antimicrobial Susceptibility Testing meeting; January 10-12, 2016; Tempe, Arizona. https://clsi.org/meetings/ast/ast-meeting-files-resources/. https://clsi.org/meetings/ast/ast-meeting-files-resources/. Arizona. Tempe, 2016; 10-12, January meeting; Testing Susceptibility Antimicrobial on Subcommittee 18. Hackel MA, Tsuji M, Yamano Y, Y, Yamano M, Tsuji MA, Hackel 2016;66(12):5575-5599. nov. fam. and nov., fam. nov., fam. Int J Syst Evol Microbiol. Evol Syst J Int Budviciaceae Morganellaceae Hafniaceae 15. 14. : an emerging global opportunistic pathogen. pathogen. opportunistic global emerging an : JS. Brooke file. on Data doi:10.1128/AAC.01076-18. 2018;62(10):e01076-18. Stenotrophomonas maltophilia Stenotrophomonas

17. : : ‘ the of taxonomy and phylogeny Genome-based RS. Gupta S, Naushad S, Alnajar M, Adeolu doi:10.1186/s13613-015-0061-0. 2015;5(1):61. Enterobacteriales’

16. . . bacilli. Gram-negative in resistance antimicrobial of Mechanisms F. Barbier PL, Woerther É, Ruppé 2012;25(1):2-41. . Ann Intensive Care Intensive Ann Rev Microbiol Clin

Echols R, Karlowsky JA, Sahm DF. Reproducibility of broth microdilution MICs for the novel siderophore cephalosporin, cefiderocol, determined using iron- using determined cefiderocol, cephalosporin, siderophore novel the for MICs microdilution broth of Reproducibility DF. Sahm JA, Karlowsky R, Echols 17. : : ‘ the of taxonomy and phylogeny Genome-based RS. Gupta S, Naushad S, Alnajar M, Adeolu doi:10.1186/s13613-015-0061-0. 2015;5(1):61. Enterobacteriales’ 12. Queenan AM, Bush K. Carbapenemases: the the Carbapenemases: K. Bush AM, Queenan 2020;26(7):S1-S3. City. York New in centers medical to endemic Microb Drug Resist. Drug Microb baumannii Acinetobacter

18. Hackel MA, Tsuji M, Yamano Y, Y, Yamano M, Tsuji MA, Hackel 2016;66(12):5575-5599. nov. fam. and nov., fam. nov., fam. Int J Syst Evol Microbiol. Evol Syst J Int Budviciaceae Morganellaceae Hafniaceae 16. . . bacilli. Gram-negative in resistance antimicrobial of Mechanisms F. Barbier PL, Woerther É, Ruppé 2012;25(1):2-41. . Ann Intensive Care Intensive Ann Rev Microbiol Clin 11. , and and , , against cefiderocol of Activity J. Quale D, Landman Z, Khan A, Iregui 2020;26(7):1-5. . Pseudomonas aeruginosa Pseudomonas Enterobacterales Resist Drug Microb

13. . . ϐ-lactamases. on perspectives present and Past K. Bush 2007;20(3):440-458. . ϐ-lactamases. versatile Antimicrob Agents Chemother Agents Antimicrob Rev Microbiol Clin

fam. nov., nov., fam. nov., fam. nov., fam. , families the into divided nov. ord. for proposal Yersiniaceae Pectobacteriaceae Erwiniaceae Enterobacteriaceae Enterobacterales 15. 14. : an emerging global opportunistic pathogen. pathogen. opportunistic global emerging an : JS. Brooke file. on Data doi:10.1128/AAC.01076-18. 2018;62(10):e01076-18. Stenotrophomonas maltophilia Stenotrophomonas endemic to medical centers in New York City. City. York New in centers medical to endemic and , , against cefiderocol of Activity J. Quale Acinetobacter baumannii Acinetobacter aeruginosa Pseudomonas Enterobacterales

17. : : ‘ the of taxonomy and phylogeny Genome-based RS. Gupta S, Naushad S, Alnajar M, Adeolu doi:10.1186/s13613-015-0061-0. 2015;5(1):61. Enterobacteriales’ 13. . . ϐ-lactamases. on perspectives present and Past K. Bush 2007;20(3):440-458. . ϐ-lactamases. versatile Antimicrob Agents Chemother Agents Antimicrob Rev Microbiol Clin 10. Iregui A, Khan Z, Landman D, D, Landman Z, Khan A, Iregui doi:10.1128/AAC.01454-17. 2018;62(1). . bacteria. Gram-negative against cephalosporin, Antimicrob Agents Chemother Agents Antimicrob

11. , and and , , against cefiderocol of Activity J. Quale D, Landman Z, Khan A, Iregui 2020;26(7):1-5. . Pseudomonas aeruginosa Pseudomonas Enterobacterales Resist Drug Microb

16. . . bacilli. Gram-negative in resistance antimicrobial of Mechanisms F. Barbier PL, Woerther É, Ruppé 2012;25(1):2-41. . Ann Intensive Care Intensive Ann Rev Microbiol Clin 12. Queenan AM, Bush K. Carbapenemases: the the Carbapenemases: K. Bush AM, Queenan 2020;26(7):S1-S3. City. York New in centers medical to endemic Microb Drug Resist. Drug Microb baumannii Acinetobacter 9. antibacterial properties of cefiderocol, a novel siderophore siderophore novel a cefiderocol, of properties antibacterial al. et M, Ota T, Sato A, Ito doi:10.1128/mBio.01541-16. 2016;7(5):e01541-16. . In vitro In mBio

15. 14. : an emerging global opportunistic pathogen. pathogen. opportunistic global emerging an : JS. Brooke file. on Data doi:10.1128/AAC.01076-18. 2018;62(10):e01076-18. Stenotrophomonas maltophilia Stenotrophomonas 11. , and and , , against cefiderocol of Activity J. Quale D, Landman Z, Khan A, Iregui 2020;26(7):1-5. . Pseudomonas aeruginosa Pseudomonas Enterobacterales Resist Drug Microb 8. Miller SI. Antibiotic resistance and regulation of the Gram-negative bacterial outer membrane barrier by host innate immune molecules. molecules. immune innate host by barrier membrane outer bacterial Gram-negative the of regulation and resistance Antibiotic SI. Miller 7396-7401.

10. Iregui A, Khan Z, Landman D, D, Landman Z, Khan A, Iregui doi:10.1128/AAC.01454-17. 2018;62(1). . bacteria. Gram-negative against cephalosporin, Antimicrob Agents Chemother Agents Antimicrob

13. . . ϐ-lactamases. on perspectives present and Past K. Bush 2007;20(3):440-458. . ϐ-lactamases. versatile Antimicrob Agents Chemother Agents Antimicrob Rev Microbiol Clin endemic to medical centers in New York City. City. York New in centers medical to endemic and , , against cefiderocol of Activity J. Quale Acinetobacter baumannii Acinetobacter aeruginosa Pseudomonas Enterobacterales . 2016;60(12): . . against activity antibacterial for systems transporter iron ferric utilizes cefiderocol Antimicrob Agents Chemother Agents Antimicrob aeruginosa Pseudomonas

12. Queenan AM, Bush K. Carbapenemases: the the Carbapenemases: K. Bush AM, Queenan 2020;26(7):S1-S3. City. York New in centers medical to endemic Microb Drug Resist. Drug Microb baumannii Acinetobacter 10. Iregui A, Khan Z, Landman D, D, Landman Z, Khan A, Iregui doi:10.1128/AAC.01454-17. 2018;62(1). . bacteria. Gram-negative against cephalosporin, Antimicrob Agents Chemother Agents Antimicrob 7. Ito A, Nishikawa T, Matsumoto S, et al. Siderophore cephalosporin cephalosporin Siderophore al. et S, Matsumoto T, Nishikawa A, Ito 7):S538-S543. 2019;69(suppl . cephalosporin. siderophore novel a of profiles Clin Infect Dis Infect Clin

11. , and and , , against cefiderocol of Activity J. Quale D, Landman Z, Khan A, Iregui 2020;26(7):1-5. . Pseudomonas aeruginosa Pseudomonas Enterobacterales Resist Drug Microb 9. antibacterial properties of cefiderocol, a novel siderophore siderophore novel a cefiderocol, of properties antibacterial al. et M, Ota T, Sato A, Ito doi:10.1128/mBio.01541-16. 2016;7(5):e01541-16. . In vitro In mBio 6. Sato T, Yamawaki K. Cefiderocol: Discovery, chemistry, and in vivo vivo in and chemistry, Discovery, Cefiderocol: K. Yamawaki T, Sato 2018;155:847-868. . relationship. activity Structure bacteria: resistant drug Eur J Med Chem Med J Eur

. 2016;60(12): . . against activity antibacterial for systems transporter iron ferric utilizes cefiderocol Antimicrob Agents Chemother Agents Antimicrob aeruginosa Pseudomonas

endemic to medical centers in New York City. City. York New in centers medical to endemic and , , against cefiderocol of Activity J. Quale Acinetobacter baumannii Acinetobacter aeruginosa Pseudomonas Enterobacterales 8. Miller SI. Antibiotic resistance and regulation of the Gram-negative bacterial outer membrane barrier by host innate immune molecules. molecules. immune innate host by barrier membrane outer bacterial Gram-negative the of regulation and resistance Antibiotic SI. Miller 7396-7401. and other Gram-negative pathogens including multi- including pathogens Gram-negative other and against activities potent exhibiting cephalosporin siderophore new A (S-649266), Pseudomonas aeruginosa Pseudomonas

10. Iregui A, Khan Z, Landman D, D, Landman Z, Khan A, Iregui doi:10.1128/AAC.01454-17. 2018;62(1). . bacteria. Gram-negative against cephalosporin, Antimicrob Agents Chemother Agents Antimicrob . 2016;60(12): . . against activity antibacterial for systems transporter iron ferric utilizes cefiderocol Antimicrob Agents Chemother Agents Antimicrob aeruginosa Pseudomonas 5. Aoki T, Yoshizawa H, Yamawaki K, et al. Cefiderocol Cefiderocol al. et K, Yamawaki H, Yoshizawa T, Aoki 2019;79(3):271-289. . bacilli. Gram-negative multidrug-resistant and carbapenem-resistant Drugs

9. antibacterial properties of cefiderocol, a novel siderophore siderophore novel a cefiderocol, of properties antibacterial al. et M, Ota T, Sato A, Ito doi:10.1128/mBio.01541-16. 2016;7(5):e01541-16. . In vitro In mBio 7. Ito A, Nishikawa T, Matsumoto S, et al. Siderophore cephalosporin cephalosporin Siderophore al. et S, Matsumoto T, Nishikawa A, Ito 7):S538-S543. 2019;69(suppl . cephalosporin. siderophore novel a of profiles Clin Infect Dis Infect Clin 4. Zhanel GG, Golden AR, Zelenistky S, et al. Cefiderocol: a siderophore cephalosporin with activity against against activity with cephalosporin siderophore a Cefiderocol: al. et S, Zelenistky AR, Golden GG, Zhanel 2009;15(17):1956-1973. . modulator. Curr Pharm Des Pharm Curr

8. Miller SI. Antibiotic resistance and regulation of the Gram-negative bacterial outer membrane barrier by host innate immune molecules. molecules. immune innate host by barrier membrane outer bacterial Gram-negative the of regulation and resistance Antibiotic SI. Miller 7396-7401. 6. Sato T, Yamawaki K. Cefiderocol: Discovery, chemistry, and in vivo vivo in and chemistry, Discovery, Cefiderocol: K. Yamawaki T, Sato 2018;155:847-868. . relationship. activity Structure bacteria: resistant drug Eur J Med Chem Med J Eur 3. Actor JK, Hwang SA, Kruzel ML. Lactoferrin as a natural immune immune natural a as Lactoferrin ML. Kruzel SA, Hwang JK, Actor 2017;105:68-78. . interactions. host-bacterial of modulation and Free Radic Biol Med Biol Radic Free

. 2016;60(12): . . against activity antibacterial for systems transporter iron ferric utilizes cefiderocol Antimicrob Agents Chemother Agents Antimicrob aeruginosa Pseudomonas and other Gram-negative pathogens including multi- including pathogens Gram-negative other and against activities potent exhibiting cephalosporin siderophore new A (S-649266), Pseudomonas aeruginosa Pseudomonas 2. 1. References: Ellermann M, Arthur JC. Siderophore-mediated iron acquisition acquisition iron Siderophore-mediated JC. Arthur M, Ellermann 2020. Inc.; Shionogi NJ: Park, Florham insert]. [package (cefiderocol) Fetroja

7. Ito A, Nishikawa T, Matsumoto S, et al. Siderophore cephalosporin cephalosporin Siderophore al. et S, Matsumoto T, Nishikawa A, Ito 7):S538-S543. 2019;69(suppl . cephalosporin. siderophore novel a of profiles Clin Infect Dis Infect Clin 5. Aoki T, Yoshizawa H, Yamawaki K, et al. Cefiderocol Cefiderocol al. et K, Yamawaki H, Yoshizawa T, Aoki 2019;79(3):271-289. . bacilli. Gram-negative multidrug-resistant and carbapenem-resistant Drugs

6. Sato T, Yamawaki K. Cefiderocol: Discovery, chemistry, and in vivo vivo in and chemistry, Discovery, Cefiderocol: K. Yamawaki T, Sato 2018;155:847-868. . relationship. activity Structure bacteria: resistant drug Eur J Med Chem Med J Eur 4. Zhanel GG, Golden AR, Zelenistky S, et al. Cefiderocol: a siderophore cephalosporin with activity against against activity with cephalosporin siderophore a Cefiderocol: al. et S, Zelenistky AR, Golden GG, Zhanel 2009;15(17):1956-1973. . modulator. Curr Pharm Des Pharm Curr

• CLSI breakpoints for Fetroja can be found in CLSI M100 CLSI in found be can Fetroja for breakpoints CLSI •

and other Gram-negative pathogens including multi- including pathogens Gram-negative other and against activities potent exhibiting cephalosporin siderophore new A (S-649266), Pseudomonas aeruginosa Pseudomonas 3. Actor JK, Hwang SA, Kruzel ML. Lactoferrin as a natural immune immune natural a as Lactoferrin ML. Kruzel SA, Hwang JK, Actor 2017;105:68-78. . interactions. host-bacterial of modulation and Free Radic Biol Med Biol Radic Free 21

5. Aoki T, Yoshizawa H, Yamawaki K, et al. Cefiderocol Cefiderocol al. et K, Yamawaki H, Yoshizawa T, Aoki 2019;79(3):271-289. . bacilli. Gram-negative multidrug-resistant and carbapenem-resistant Drugs 2. 1. References: Ellermann M, Arthur JC. Siderophore-mediated iron acquisition acquisition iron Siderophore-mediated JC. Arthur M, Ellermann 2020. Inc.; Shionogi NJ: Park, Florham insert]. [package (cefiderocol) Fetroja

• FDA breakpoints for Fetroja can be found at FDA/STIC at found be can Fetroja for breakpoints FDA •

• CLSI breakpoints for Fetroja can be found in CLSI M100 CLSI in found be can Fetroja for breakpoints CLSI • 4. Zhanel GG, Golden AR, Zelenistky S, et al. Cefiderocol: a siderophore cephalosporin with activity against against activity with cephalosporin siderophore a Cefiderocol: al. et S, Zelenistky AR, Golden GG, Zhanel 2009;15(17):1956-1973. . modulator. Curr Pharm Des Pharm Curr

20 21

• CLSI breakpoints for Fetroja can be found in CLSI M100 CLSI in found be can Fetroja for breakpoints CLSI •

21 2. 1. References: Ellermann M, Arthur JC. Siderophore-mediated iron acquisition acquisition iron Siderophore-mediated JC. Arthur M, Ellermann 2020. Inc.; Shionogi NJ: Park, Florham insert]. [package (cefiderocol) Fetroja • Breakpoints are based on a dosage regimen of 2 grams every 8 hours administered over 3 hours 3 over administered hours 8 every grams 2 of regimen dosage a on based are Breakpoints • • FDA breakpoints for Fetroja can be found at FDA/STIC at found be can Fetroja for breakpoints FDA •

• FDA breakpoints for Fetroja can be found at FDA/STIC at found be can Fetroja for breakpoints FDA •

• CLSI breakpoints for Fetroja can be found in CLSI M100 CLSI in found be can Fetroja for breakpoints CLSI • 20

• Breakpoints are based on a dosage regimen of 2 grams every 8 hours administered over 3 hours 3 over administered hours 8 every grams 2 of regimen dosage a on based are Breakpoints • susceptibility testing susceptibility 21

• Breakpoints are based on a dosage regimen of 2 grams every 8 hours administered over 3 hours 3 over administered hours 8 every grams 2 of regimen dosage a on based are Breakpoints •

• FDA breakpoints for Fetroja can be found at FDA/STIC at found be can Fetroja for breakpoints FDA •

susceptibility testing susceptibility 20

FDA and CLSI recommendations for Fetroja antibiotic antibiotic Fetroja for recommendations CLSI and FDA

susceptibility testing susceptibility • Breakpoints are based on a dosage regimen of 2 grams every 8 hours administered over 3 hours 3 over administered hours 8 every grams 2 of regimen dosage a on based are Breakpoints •

FDA and CLSI recommendations for Fetroja antibiotic antibiotic Fetroja for recommendations CLSI and FDA

FDA and CLSI recommendations for Fetroja antibiotic antibiotic Fetroja for recommendations CLSI and FDA susceptibility testing susceptibility

(Total iron, mg/L) iron, (Total

FDA and CLSI recommendations for Fetroja antibiotic antibiotic Fetroja for recommendations CLSI and FDA

1.02 10.02 0.52 0.32 0.20 0.12 0.07 0.05 0.03 0.02

(Total iron, mg/L) iron, (Total 0

available Mueller-Hinton broth Mueller-Hinton available

1.02 10.02 0.52 0.32 0.20 0.12 0.07 0.05 0.03 0.02 (Total iron, mg/L) iron, (Total 7,18

0 prepared using commercially commercially using prepared 1.02

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• ID-CAMHB media can be be can media ID-CAMHB •

available Mueller-Hinton broth Mueller-Hinton available P aeruginosa MIC (μg/mL)

prepared using commercially commercially using prepared

0.2 7,18

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0.4

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19 CAMHB ID-CAMHB

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≤ 0.03 μg/mL) μg/mL) 0.03 content (iron

dilution method for Fetroja Fetroja for method dilution 0.6

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dilution method for Fetroja Fetroja for method dilution 0.6 0.8

with additional iron additional with

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with additional iron additional with

1.2

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ID-CAMHB ID-CAMHB ID-CAMHB CAMHB

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Concentration of iron plays a critical role in the determination of Fetroja MICs Fetroja of determination the in role critical a plays iron of Concentration

1.2

with additional iron additional with

Cefiderocol (siderophore + porin uptake) porin + (siderophore Cefiderocol

ID-CAMHB ID-CAMHB ID-CAMHB CAMHB Concentration of iron plays a critical role in the determination of Fetroja MICs Fetroja of determination the in role critical a plays iron of Concentration

Cefiderocol (siderophore + porin uptake) porin + (siderophore Cefiderocol

7 1.2

leading to active Fetroja uptake Fetroja active to leading

Concentration of iron plays a critical role in the determination of Fetroja MICs Fetroja of determination the in role critical a plays iron of Concentration

7 18

Cefiderocol (siderophore + porin uptake) porin + (siderophore Cefiderocol

leading to active Fetroja uptake Fetroja active to leading

During infection, human plasma has very low available iron, iron, available low very has plasma human infection, During

Concentration of iron plays a critical role in the determination of Fetroja MICs Fetroja of determination the in role critical a plays iron of Concentration

7 leading to active Fetroja uptake Fetroja active to leading

During infection, human plasma has very low available iron, iron, available low very has plasma human infection, During

During infection, human plasma has very low available iron, iron, available low very has plasma human infection, During leading to active Fetroja uptake Fetroja active to leading

18 During infection, human plasma has very low available iron, iron, available low very has plasma human infection, During Available susceptibility testing methods for Fetroja A closer look into Fetroja for microbiologists FetrojaFetroja overcomes overcomes the 3 major3 major, mechanisms often coexisting, of Gram-negative Fetroja® (cefiderocol) HardyDisk™ resistance carbapenem mechanisms resistance1,10,11,22-24 The world’s only siderophore cephalosporin—uses iron 1 FetrojaFetroja remains passively andactive activ inely the ente rpresences cells…1,4 of all these mechanisms,...and overcomes which resi softentance coexist in to gain bacterial cell entry, along with passive porin entry hard-to-treat pathogens such as A baumannii complex and P aeruginosa1, 11, 22-25 Cefiderocol 30 µg disk: Fetroja remains active against all of these mechanisms To survive in the host environment, bacteria use siderophores to actively uptake iron2,3 • Visit www.hardydiagnostics.com or call 1-800-266-2222 to order Active transport allows for an additional Overcomes porin channel changes by Overcomes efflux pump method of entry into bacterial cells7 entering through the iron transport system1,4 up-regulation1,9-11 • Catalog numbers: single pack, Z9431; 5-pack, Z9435 Fetroja OTHER Bacteria 1 Bacterial growth 3 Bacteria respond to low iron concentration LACTAMS Fetroja IRON depends on and produce iron-binding siderophores Disk-diffusion method for cefiderocol is standardized to be performed on regular inactivates drug Fe expels -lactams available free iron PORINStable against all classes Active against isolates that Mueller-Hinton agar plates Fe CHANNEL(A, B, C, and D) of IRON TRANSPORT-lactamase SYSTEM Efflux pumpALTERED PORIN CHANNELare resistant due to efflux -lactamases, including 1,9-11 Fe hydrolysis up-regulation pump up-regulation Gra serine-carbapenemases m- OUTER MEMBRANE ne and metallo--lactamases ga 9,26 tiv PERIPLASM (VIM, IMP, and NDM) e b USFET-0306 02/21 a LACTAM c Fetroja DEGRADATION Immune cells such as t PASSIVE DIFFUSION ACTIVE TRANSPORT Stable against Maintains activity e r neutrophils i Fe Porin channel all classes of despite efflux pump a up-regulation1,9-11 changes ϐ-lactamases Active against pathogens (A, B, C, and D)1 Fe Iron-bound siderophores ™ PEPTIDOGLYCAN that have a decrease or change 4 1,9,26 are then actively Thermo Scientific in porin channels Fe Fe Fe Iron transported into the cell ™ EFFLUX PUMP Photograph used courtesy of Thermo Fisher limit drug access 2 In response to infection, to allow growth Sensititre MIC Plates Scientific; copying prohibited. Fe host cells produce iron-binding Fe lactoferrin to sequester iron Plates including cefiderocol (MIC range: 0.03–32 µg/mL): • Visit www.thermofisher.com/AST or email your local representative at INNER MEMBRANE Fe LEARN MORE AT [email protected] to order PENICILLINBINDING PROTEINS Adapted fFetroja.comrom Zhanel et al. • Catalog numbers: MDRGN2F, MDRGNX2F (with colistin)–10 plates/box Exact mechanisms Fe and transporters Lactoferrin IMPORTANT• The unique SAFETY structure INFORMATION of Fetroja allows (continued) it to remain stable against all classes of ϐ-lactamases1,5 may vary across Standard Sensititre Mueller-Hinton broth is used for inoculation Bacterial siderophore pathogens WARNINGS AND PRECAUTIONS (continued) INDICATIONS Development• Fetroja is of able Drug-Resistant to overcome Bacteria porin channel changes as it also enters through the active iron transport system1,4,9 Fetroja® (cefiderocol) is indicated in patients 18 years of age or older for the treatment of complicated Prescribing Fetroja in the absence of a proven or strongly suspected bacterial infection or a prophylactic urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible Gram-negative USFET-0306 02/21 indication• Fetroja is unlikely is active to against provide isolates benefit tothat the are patient resistant and increases due to efflux the riskpump of up-regulationthe development1,9-11 of drug- microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and resistant bacteria. Enterobacter cloacae complex. ADVERSE REACTIONS IMPORTANT SAFETY INFORMATION (continued) Fetroja is indicated in patients 18 years of age or older for the treatment of hospital-acquired bacterial Laboratory Specialists, Inc. (LSI) The most common adverse reactions occurring in (≥2%) of patients receiving Fetroja compared to imipenem/ pneumonia and ventilator-associated bacterial pneumonia, caused by the following susceptible Gram- cilastatinWARNINGS in the cUTIAND trialPRECAUTIONS were: diarrhea (continued) (4% vs 6%), infusion site reactions (4% vs 5%), constipation (3% negative microorganisms: Acinetobacter baumannii complex, Escherichia coli, Enterobacter cloacae Panel of Isolates vs 4%),Increase rash (3%in All-Cause vs <1%), candidiasisMortality in (2% Patients vs 3%), with cough Carbapenem-Resistant (2% vs <1%), elevations Gram-Negative in liver tests (2% vs <1%), complex, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens. headacheBacterial (2% Infections vs 5%), hypokalemia (continued) (2% vs 3%), nausea (2% vs 4%), and vomiting (2% vs 1%). The most USAGE • Visit www.labspec.org, email your local representative at [email protected], common adverse reactions occurring in (≥4%) of patients receiving Fetroja compared to meropenem in the HABP/VABPThe increase trial in were: all-cause elevations mortality in liver occurred tests (16% in patients vs 16%), treated hypokalemia for nosocomial (11% vs pneumonia,15%), diarrhea bloodstream (9% vs 9%), To reduce the development of drug-resistant bacteria and maintain the effectiveness of Fetroja and or call (440) 835-4458 to order hypomagnesemiainfections, or sepsis. (5% vs The <1%), 28-Day and atrial all-cause fibrillation mortality (5% was vs 3%). higher in patients treated with Fetroja than other antibacterial drugs, Fetroja should be used only to treat or prevent infections that are proven or in patients treated with BAT [25/101 (24.8%) vs 9/49 (18.4%), treatment difference 6.4%, 95% CI (-8.6, strongly suspected to be caused by susceptible bacteria. CONTRAINDICATIONS19.2)]. All-cause mortality remained higher in patients treated with Fetroja than in patients treated with Shionogi has collaborated with LSI to develop a panel of isolates for laboratories to FetrojaBAT isthrough contraindicated Day 49 [34/101 in patients (33.7%) with vs a10/49 known (20.4%), history treatment of severe differencehypersensitivity 13.3%, to 95% cefiderocol CI (-2.5, or 26.9)]. other IMPORTANT SAFETY INFORMATION beta-lactam antibacterial drugs, or any other component of Fetroja. perform verification and validation Generally, deaths were in patients with infections caused by Gram-negative organisms, including non- CONTRAINDICATIONS Pleasefermenters see additional such as Important Acinetobacter Safety baumannii Information complex, throughout Stenotrophomonas and enclosedFull Prescribing maltophilia Full Prescribing, Informationand Pseudomonas Fetroja is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or Informationaeruginosa for, and Fetroja were inthe pocket. result of worsening or complications of infection, or underlying comorbidities. other beta-lactam antibacterial drugs, or any other component of Fetroja. for TheFetroja cause located of the atincrease the end. in mortality has not been established. Please see additional Important Safety Information throughout and enclosed Full Prescribing Closely monitor the clinical© 2021 Shionogi response Inc. Florham to therapy Park, NJ 07932. in Allpatients Rights Reserved. with Fetroja cUTI is is a aand registered registered HABP/VABP. trademark trademark of of Shionogi Shionogi & & Co., Co., Ltd. Ltd. Osaka, Osaka, Japan. Japan. All other trademarks areare the the property property of of their their respective respective owners. owners. USFET-0307 USFET-0306 02/2102/21 Information for Fetroja in pocket.

USFET-0306 02/21 3 9