During infection, human plasma has very low available iron, leading to active Fetroja uptake18 Concentration of iron plays a critical role in the determination of Fetroja MICs7 Cefiderocol (siderophore + porin uptake) 1.2 CAMHB ID-CAMHB ID-CAMHB with additional iron 1 CLSI has approved ID-CAMHB (iron content ≤0.03 μg/mL) 0.8 media for the microbroth MIC (μg/mL) 0.6 ID-CAMHB CAMHB dilution method for Fetroja (≤0.03 μg/mL) (~0.2 μg/mL) MIC testing19 0.4 P aeruginosa • ID-CAMHB media can be 0.2 prepared using commercially available Mueller-Hinton broth7,18 0 0.02 0.03 0.05 0.07 0.12 0.20 0.32 0.52 1.02 10.02 (Total iron, mg/L) FDA and CLSI recommendations for Fetroja antibiotic susceptibility testing • Breakpoints are based on a dosage regimen of 2 grams every 8 hours administered over 3 hours • FDA breakpoints for Fetroja can be found at FDA/STIC20 • CLSI breakpoints for Fetroja can be found in CLSI M10021 References: 1. Fetroja (cefiderocol) [package insert]. Florham Park, NJ: Shionogi Inc.; 2020. 2. Ellermann M, Arthur JC. Siderophore-mediated iron acquisition and modulation of host-bacterial interactions. Free Radic Biol Med. 2017;105:68-78. 3. Actor JK, Hwang SA, Kruzel ML. Lactoferrin as a natural immune modulator. Curr Pharm Des. 2009;15(17):1956-1973. 4. Zhanel GG, Golden AR, Zelenistky S, et al. Cefiderocol: a siderophore cephalosporin with activity against carbapenem-resistant and multidrug-resistant Gram-negative bacilli. Drugs. 2019;79(3):271-289. 5. Aoki T, Yoshizawa H, Yamawaki K, et al. Cefiderocol (S-649266), A new siderophore cephalosporin exhibiting potent activities against Pseudomonas aeruginosa and other Gram-negative pathogens including multi- drug resistant bacteria: Structure activity relationship. Eur J Med Chem. 2018;155:847-868. 6. Sato T, Yamawaki K. Cefiderocol: Discovery, chemistry, and in vivo profiles of a novel siderophore cephalosporin. Clin Infect Dis. 2019;69(suppl 7):S538-S543. 7. Ito A, Nishikawa T, Matsumoto S, et al. Siderophore cephalosporin cefiderocol utilizes ferric iron transporter systems for antibacterial activity against Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2016;60(12): 7396-7401. 8. Miller SI. Antibiotic resistance and regulation of the Gram-negative bacterial outer membrane barrier by host innate immune molecules. mBio. 2016;7(5):e01541-16. doi:10.1128/mBio.01541-16. 9. Ito A, Sato T, Ota M, et al. In vitro antibacterial properties of cefiderocol, a novel siderophore cephalosporin, against Gram-negative bacteria. Antimicrob Agents Chemother. 2018;62(1). doi:10.1128/AAC.01454-17. 10. Iregui A, Khan Z, Landman D, Quale J. Activity of cefiderocol against Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii endemic to medical centers in New York City. Microb Drug Resist. 2020;26(7):1-5. 11. Iregui A, Khan Z, Landman D, Quale J. Activity of cefiderocol against Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii endemic to medical centers in New York City. Microb Drug Resist. 2020;26(7):S1-S3. 12. Queenan AM, Bush K. Carbapenemases: the versatile ϐ-lactamases. Clin Microbiol Rev. 2007;20(3):440-458. 13. Bush K. Past and present perspectives on ϐ-lactamases. Antimicrob Agents Chemother. 2018;62(10):e01076-18. doi:10.1128/AAC.01076-18. 14. Data on file. 15. Brooke JS. Stenotrophomonas maltophilia: an emerging global opportunistic pathogen. Clin Microbiol Rev. 2012;25(1):2-41. 16. Ruppé É, Woerther PL, Barbier F. Mechanisms of antimicrobial resistance in Gram-negative bacilli. Ann Intensive Care. 2015;5(1):61. doi:10.1186/s13613-015-0061-0. 17. Adeolu M, Alnajar S, Naushad S, Gupta RS. Genome-based phylogeny and taxonomy of the ‘Enterobacteriales’: proposal for Enterobacterales ord. nov. divided into the families Enterobacteriaceae, Erwiniaceae fam. nov., Pectobacteriaceae fam. nov., Yersiniaceae fam. nov., Hafniaceae fam. nov., Morganellaceae fam. nov., and Budviciaceae fam. nov. Int J Syst Evol Microbiol. 2016;66(12):5575-5599. 18. Hackel MA, Tsuji M, Yamano Y, Echols R, Karlowsky JA, Sahm DF. Reproducibility of broth microdilution MICs for the novel siderophore cephalosporin, cefiderocol, determined using iron- depleted cation-adjusted Mueller-Hinton broth. Diagn Microbiol Infect Dis. 2019;94(4):321-325. 19. Clinical and Laboratory Standards Institute. Summary minutes: Subcommittee on Antimicrobial Susceptibility Testing meeting; January 10-12, 2016; Tempe, Arizona. https://clsi.org/meetings/ast/ast-meeting-files-resources/. Accessed August 28, 2020. 20. US Food and Drug Administration. Cefiderocol injection. https://www.fda.gov/drugs/development-resources/cefiderocol-injection. Updated November 20, 2019. Accessed August 28, 2020. 21. CLSI. Performance Standards for Antimicrobial Susceptibility Testing. 29th ed. CLSI supplement M100. Wayne, PA: Clinical and Laboratory Standards Institute; 2019. 22. Davies TA, Queenan AM, Morrow BJ, et al. Longitudinal survey of carbapenem resistance and resistance mechanisms in Enterobacteriaceae and non-fermenters from the USA in 2007–09. J Antimicrob Chemother. 2011;66(10):2298-2307. 23. Perez F, Hujer AM, Hujer KM, Becker BK, Rather PN, Bonomo RA. Global challenge of multidrug-resistant Acinetobacter baumannii. Antimicrob Agents Chemother. 2007;51(10):3471-3484. 24. Rodríguez-Martínez JM, Poirel L, Nordmann P. Molecular epidemiology and mechanisms of carbapenem resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2009;53(11):4783-4788. 25. Fernández L, Hancock REW. Adaptive and mutational resistance: role of porins and efflux pumps in drug resistance. Clin Microbiol Rev. 2012;25(4):661-681. 26. Kazmierczak KM, Tsuji M, Wise MG, et al. In vitro activity of cefiderocol, a siderophore cephalosporin, against a recent collection of clinically relevant carbapenem-non-susceptible Gram-negative bacilli, including serine carbapenemase- and metallo-ϐ-lactamase-producing isolates (SIDERO-WT-2014 Study). Int J Antimicrob Agents. 2019;53(2):177-184. 7 USFET-0306 02/21 USFET-0306 for Fetroja located at the end. end. the at located Fetroja for 1 Information for Fetroja in pocket. in Fetroja for Information All other trademarks are the property of their respective owners. USFET-0306 02/21 USFET-0306 owners. respective their of property the are trademarks other All Please see additional Important Safety Information throughout and Full Prescribing Information Information Prescribing Full and throughout Information Safety Important additional see Please is a registered trademark of Shionogi & Co., Ltd. Osaka, Japan. Japan. Osaka, Ltd. Co., & Shionogi of trademark registered a is Fetroja Reserved. Rights All 07932. NJ Park, Florham Inc. Shionogi 2021 © Please see additional Important Safety Information throughout and enclosed Full Prescribing Prescribing Full enclosed and throughout Information Safety Important additional see Please other beta-lactam antibacterial drugs, or any other component of Fetroja. of component other any or drugs, antibacterial beta-lactam other Information for Fetroja in pocket. in Fetroja for Information Fetroja is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or or cefiderocol to hypersensitivity severe of history known a with patients in contraindicated is Fetroja Please see additional Important Safety Information throughout and enclosed Full Prescribing Prescribing Full enclosed and throughout Information Safety Important additional see Please CONTRAINDICATIONS perform verification and validation and verification perform beta-lactam antibacterial drugs, or any other component of Fetroja. of component other any or drugs, antibacterial beta-lactam Shionogi has collaborated with LSI to develop a panel of isolates for laboratories to to laboratories for isolates of panel a develop to LSI with collaborated has Shionogi IMPORTANT SAFETY INFORMATION SAFETY IMPORTANT Fetroja is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or other other or cefiderocol to hypersensitivity severe of history known a with patients in contraindicated is Fetroja CONTRAINDICATIONS CONTRAINDICATIONS strongly suspected to be caused by susceptible bacteria. bacteria. susceptible by caused be to suspected strongly hypomagnesemia (5% vs <1%), and atrial fibrillation (5% vs 3%). vs (5% fibrillation atrial and <1%), vs (5% hypomagnesemia other antibacterial drugs, Fetroja should be used only to treat or prevent infections that are proven or or proven are that infections prevent or treat to only used be should Fetroja drugs, antibacterial other or call (440) 835-4458 to order to 835-4458 (440) call or HABP/VABP trial were: elevations in liver tests (16% vs 16%), hypokalemia (11% vs 15%), diarrhea (9% vs 9%), 9%), vs (9% diarrhea 15%), vs (11% hypokalemia 16%), vs (16% tests liver in elevations were: trial HABP/VABP To reduce the development of drug-resistant bacteria and maintain the effectiveness of Fetroja and and Fetroja of effectiveness the maintain and bacteria drug-resistant of development the reduce To • Visit www.labspec.org, email your local representative at [email protected], [email protected], at representative local your email www.labspec.org, Visit • ≥ 4%) of patients receiving Fetroja compared to meropenem in the the in meropenem to compared Fetroja receiving patients of 4%) ( in occurring reactions adverse common USAGE headache (2% vs 5%), hypokalemia (2% vs 3%), nausea (2% vs 4%), and vomiting (2% vs 1%). The most most The 1%). vs (2% vomiting and 4%), vs (2% nausea 3%), vs (2% hypokalemia 5%), vs (2% headache