Комбинация цефидерокола и сульбактама против карбапенеморезистентных Enterobacterales: механизмы синергизма и перспективы клинического применения

Введение. Распространение карбапенеморезистентных Enterobacterales сопровождается высокой летальностью, ограничением терапевтических возможностей и риском неэффективности стартовой антибактериальной терапии. Цефидерокол сохраняет активность в отношении многих продуцентов сериновых карбапенемаз и металло-β-лактамаз благодаря использованию бактериальных систем транспорта железа. Однако гиперпродукция β-лактамаз, изменения сидерофорных рецепторов и PBP3, а также гетерорезистентность могут снижать его эффективность. Одним из потенциальных подходов к усилению активности цефидерокола является его сочетание с сульбактамом.

Цель. Обобщить и критически оценить данные о механизмах синергизма цефидерокола и сульбактама в отношении карбапенеморезистентных Enterobacterales, имеющейся экспериментальной и клинической доказательной базе, ограничениях и перспективах применения комбинации.

Материал и методы. Обзор подготовлен с учётом критериев SANRA и PRISMA-S. Поиск проводился в PubMed/MEDLINE, SpringerLink, ScienceDirect, eLIBRARY.ru, CyberLeninka и Google Scholar за период 2007–2026 гг. Анализировались исследования механизмов резистентности к цефидероколу, ингибирующей и PBP-опосредованной активности сульбактама, микробиологического синергизма, гетерорезистентности, ФК/ФД-характеристик, доклинической эффективности и клинического применения препаратов. В итоговый анализ включены 92 публикации.

Результаты. Потенциальный синергизм может реализовываться посредством уменьшения гидролиза цефидерокола ингибируемыми сериновыми β-лактамазами, повышения его периплазматической экспозиции, возможного дополнительного воздействия на PBP и подавления отдельных устойчивых субпопуляций. Вместе с тем сульбактам не ингибирует металло-β-лактамазы и обладает ограниченной активностью против KPC- и OXA-48-подобных ферментов. Он не компенсирует нарушения железотранспорта, изменения PBP3 и другие неферментативные механизмы устойчивости. Прямое исследование комбинации при CRE включало лишь два изолята K. pneumoniae. Репрезентативные исследования на коллекциях Enterobacterales, динамические ФК/ФД-модели, прямые исследования in vivo и клинические испытания отсутствуют. Не установлены оптимальная экспозиция сульбактама, предикторы ответа и стандартизированные критерии лабораторного подтверждения синергизма.

Заключение. Комбинация цефидерокола и сульбактама имеет экспериментальное механистическое обоснование, однако имеющихся данных недостаточно для её рутинного применения при инфекциях, вызванных карбапенеморезистентными Enterobacterales. Доказательств недостаточно для определения терапевтической ниши комбинации, включая её использование в качестве спасительной терапии. До получения воспроизводимых микробиологических, ФК/ФД-, доклинических и клинических данных сочетание следует рассматривать исключительно как объект дальнейших исследований. Для клинической трансляции необходимы механизм-стратифицированные микробиологические, ФК/ФД-, доклинические и клинические исследования.

1. World Health Organization. WHO bacterial priority pathogens list, 2024: bacterial pathogens of public health importance to guide research, development and strategies to prevent and control antimicrobial resistance. Geneva: World Health Organization; 2024.

2. World Health Organization. Global antibiotic resistance surveillance report 2025: WHO Global Antimicrobial Resistance and Use Surveillance System (GLASS). Geneva: World Health Organization; 2025.

3. European Centre for Disease Prevention and Control. Carbapenem-resistant Enterobacterales, third update – 3 February 2025. Stockholm: ECDC; 2025. doi: 10.2900/8752612.

4. Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. 2022; 399 (10325): 629–655. doi: 10.1016/S0140-6736(21)02724-0.

5. Jean SS, Harnod D, Hsueh PR. Global threat of carbapenem-resistant Gram-negative bacteria. Front Cell Infect Microbiol. 2022; 12: 823684. doi: 10.3389/fcimb.2022.823684.

6. Wang M, Earley M, Chen L, et al.; Multi-Drug Resistant Organism Network Investigators. Clinical outcomes and bacterial characteristics of carbapenem-resistant Klebsiella pneumoniae complex among patients from different global regions (CRACKLE-2): a prospective, multicentre, cohort study. Lancet Infect Dis. 2022; 22 (3): 401–412. doi: 10.1016/S1473-3099(21)00399-6.

7. van Duin D, Arias CA, Komarow L, et al.; Multi-Drug Resistant Organism Network Investigators. Molecular and clinical epidemiology of carbapenem-resistant Enterobacterales in the USA (CRACKLE-2): a prospective cohort study. Lancet Infect Dis. 2020; 20 (6): 731–741. doi: 10.1016/S1473–3099(19)30755-8.

8. Lin Q, Wu M, Yu H, Jia X, Zou H, Ma D, et al. Clinical and microbiological characterization of carbapenem-resistant Enterobacteriales: a prospective cohort study. Front Pharmacol. 2021; 12: 716324. doi: 10.3389/fphar.2021.716324.

9. Palacios-Baena ZR, Giannella M, Manissero D, Rodriguez-Bafio J, Viale R, et al. Risk factors for carbapenem-resistant Gram-negative bacterial infections: a systematic review. Clin Microbiol Infect. 2021; 27 (2): 228–235. doi: 10.1016/j.cmi.2020.10.016.

10. Qian Y, Bi Y, Liu S, Li X, Dong S, Ju M. Predictors of mortality in patients with carbapenem-resistant Klebsiella pneumoniae infection: a meta-analysis and a systematic review. Ann Palliat Med. 2021; 10 (7): 7340–7350. doi: 10.21037/apm-21-338.

11. Tamma PD, Heil EL, Justo JA, Mathers AJ, Satlin MJ, Bonomo RA. Infectious Diseases Society of America 2024 guidance on the treatment of antimicrobial-resistant Gram-negative infections. Clin Infect Dis. 2024: ciae403. doi: 10.1093/cid/ciae403.

12. Paul M, Carrara E, Retamar P, Tängden T, BittermanR, Bonomo RA, et al. European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines for the treatment of infections caused by multidrug-resistant Gram-negative bacilli, endorsed by the European Society of Intensive Care Medicine. Clin Microbiol Infect. 2022; 28 (4): 521–547. doi: 10.1016/j.cmi.2021.11.025.

13. Reyes S, Nicolau DP. Precision medicine for the diagnosis and treatment of carbapenem-resistant Enterobacterales: time to think from a different perspective. Expert Rev Anti Infect Ther. 2020; 18 (8): 721-'740. doi: 10.1080/14787210.2020.1760844.

14. Gatti M, Viaggi B, Rossolini GM, Pea F, Viale P. An evidence-based multidisciplinary approach focused at creating algorithms for targeted therapy of BSIs, cUTIs, and cIAIs caused by Enterobacterales in critically ill adult patients. Infect Drug Resist. 2021; 14: 2461–2498. doi: 10.2147/IDR.S314241.

15. van Duin D, Lok JJ, Earley M, Cober E, Richter S, Perez F, et al.; Antibacterial Resistance Leadership Group. Colistin versus ceftazidime-avibactam in the treatment of infections due to carbapenem-resistant Enterobacteriaceae. Clin Infect Dis. 2018; 66 (2): 163–171. doi: 10.1093/cid/cix783.

16. Shields RK, Nguyen MH, Chen L, Press EG, Potoski BA, Marini RV, et al. Ceftazidime-avibactam is superior to other treatment regimens against carbapenem-resistant Klebsiella pneumoniae bacteremia. Antimicrob Agents Chemother. 2017; 61 (8): e00883–17. doi: 10.1128/AAC.00883-17.

17. Wunderink RG, Giamarellos-Bourboulis EJ, Rahav G, Mathers AJ, Bassetti M, Vazguez J, et al. Effect and safety of meropenem-vaborbactam versus best-available therapy in patients with carbapenem-resistant Enterobacteriaceae infections: the TANGO II randomized clinical trial. Infect Dis Ther. 2018; 7 (4): 439–455. doi: 10.1007/s40121-018-0214-1.

18. Motsch J, Murta de Oliveira C, Stus V, et al. RESTORE-IMI 1: a multicenter, randomized, double-blind trial comparing efficacy and safety of imipenem/relebactam versus colistin plus imipenem in patients with imipenem-nonsusceptible bacterial infections. Clin Infect Dis. 2020; 70 (9): 1799–1808. doi: 10.1093/cid/ciz530.

19. McKinnell JA, Dwyer JP, Talbot GH, Connolly LE, Friedland I, Smith A, et al.; CARE Study Group. Plazomicin for infections caused by carbapenem-resistant Enterobacteriaceae. N Engl J Med. 2019; 380 (8): 791–793. doi: 10.1056/NEJMc1807634.

20. Ackley R, Roshdy D, Meredith J, Minor S, Anderson WE, Capraro G, Polk C. Meropenem-vaborbactam versus ceftazidime-avibactam for treatment of carbapenem-resistant Enterobacteriaceae infections. Antimicrob Agents Chemother. 2020; 64 (5): e02313–19. doi: 10.1128/AAC.02313-19.

21. Doi Y. Treatment options for carbapenem-resistant Gram-negative bacterial infections. Clin Infect Dis. 2019; 69 (Suppl 7): S565–S575. doi: 10.1093/cid/ciz830.

22. Emeraud C, Escaut L, Boucly A, Fortineau N, Bonnin RA, Naas T, Dortet L. Aztreonam plus clavulanate, tazobactam, or avibactam for treatment of infections caused by metallo-β-lactamase-producing Gram-negative bacteria. Antimicrob Agents Chemother. 2019; 63 (5): e00010–19. doi: 10.1128/AAC.00010-19.

23. Karakonstantis S, Rousaki M, Kritsotakis EI. Cefiderocol: systematic review of mechanisms of resistance, heteroresistance and in vivo emergence of resistance. Antibiotics (Basel). 2022; 11 (6): 723. doi: 10.3390/antibiotics11060723.

24. Klein S, Boutin S, Kocer K, Fiedler MO, Störzinger D, Weigand M, et al. Rapid development of cefiderocol resistance in carbapen-resistant Enterobacter cloacae during therapy is associated with heterogeneous mutations in the catecholate siderophore receptor cirA. Clin Infect Dis. 2022; 74 (5): 905–908. doi: 10.1093/cid/ciab511.

25. Simner PJ, Mostafa HH, Bergman Y, Ante Y, Tekle T, Adebayo A, et al. Progressive development of cefiderocol resistance in Escherichia coli during therapy is associated with increased blaNDM-5 copy number and gene expression. Clin Infect Dis. 2022; 75 (1): 47–54. doi: 10.1093/cid/ciab888.

26. Kawai A, McElheny CL, Iovleva A, Kline E, Sluis-Cremer N, Shields RK, Doi Y. Structural basis of reduced susceptibility to ceftazidime-avibactam and cefiderocol in Enterobacter cloacae due to AmpC R2 loop deletion. Antimicrob Agents Chemother. 2020; 64 (7): e00198–20. doi: 10.1128/AAC.00198-20.

27. Nurjadi D, Kocer K, Chanthalangsy Q, Klein S, Heeg K, Boutin S. New Delhi metallo-β-lactamase facilitates the emergence of cefiderocol resistance in Enterobacter cloacae. Antimicrob Agents Chemother. 2022; 66 (2): e0201121. doi: 10.1128/AAC.02011-21.

28. McElheny CL, Fowler EL, Iovleva A, Shields RK, Doi Y. In vitro evolution of cefiderocol resistance in an NDM-producing Klebsiella pneumoniae due to functional loss of cirA. Microbiol Spectr. 2021; 9 (3): e0177921. doi: 10.1128/Spectrum.01779-21.

29. Nordmann P, Shields RK, Doi Y, Takemura M, Echols R, Matsunaga Y, Yamano Y. Mechanisms of reduced susceptibility to cefiderocol among isolates from the CREDIBLE-CR and APEKS-NP clinical trials. Microb Drug Resist. 2022; 28 (4): 398–407. doi: 10.1089/mdr.2021.0180.

30. Shields RK, Iovleva A, Kline EG, Kawai A, McElheny CL, Doi Y. Clinical evolution of AmpC-mediated ceftazidime-avibactam and cefiderocol resistance in Enterobacter cloacae complex following exposure to cefepime. Clin Infect Dis. 2020; 71 (10): 2713–2716. doi: 10.1093/cid/ciaa355.

31. Bianco G, Boattini M, Comini S, Iannaccone M, Bondi A, Cavallo R, Costa C. In vitro activity of cefiderocol against ceftazidime-avibactam-susceptible and -resistant KPC-producing Enterobacterales: cross-resistance and synergistic effects. Eur J Clin Microbiol Infect Dis. 2022; 41 (1): 63–70. doi: 10.1007/s10096-021-04341-z.

32. Poirel L, Sadek M, Kusaksizoglu A, Nordmann P. Co-resistance to ceftazidime-avibactam and cefiderocol in clinical isolates producing KPC variants. Eur J Clin Microbiol Infect Dis. 2022; 41 (4): 677–680. doi: 10.1007/s10096-021-04397-x.

33. Hobson CA, Cointe A, Jacquier H, Choudhury A, Magnan M, Courroux C, et al. Cross-resistance to cefiderocol and ceftazidime-avibactam in KPC β-lactamase mutants and the inoculum effect. Clin Microbiol Infect. 2021; 27 (8): 1172.e7–1172.e10. doi: 10.1016/j.cmi.2021.04.016.

34. Price TK, Davar K, Contreras D, Ward KW, Garner OB, Simner PJ et al. Case report and genomic analysis of cefiderocol-resistant Escherichia coli clinical isolates. Am J Clin Pathol. 2022; 157 (2): 257–265. doi: 10.1093/ajcp/aqab115.

35. Lan P, Lu Y, Chen Z, Wu X, Hua X, Jiang Y, et al. Emergence of high-level cefiderocol resistance in carbapenem-resistant Klebsiella pneumoniae from bloodstream infections in patients with hematologic malignancies in China. Microbiol Spectr. 2022; 10 (2): e0008422. doi: 10.1128/spectrum.00084-22.

36. Jousset AB, Poignon C, Yilmaz S, Bleibtreu A, Emeraud C, Girlich D, et al. Rapid selection of a cefiderocol-resistant Escherichia coli producing NDM-5 associated with a single amino acid substitution in the CirA siderophore receptor. J Antimicrob Chemother. 2023; 78 (4): 1125–1127. doi: 10.1093/jac/dkad004.

37. Sato T, Ito A, Ishioka Y, Matsumoto S, Rokushima M, Karmierczak KM, et al. Escherichia coli strains possessing a four-amino-acid YRIN insertion in PBP3 identified as part of the SIDERO-WT-2014 surveillance study. JAC Antimicrob Resist. 2020; 2 (3): dlaa081. doi: 10.1093/jacamr/dlaa081.

38. Wang Q, Jin L, Sun S, Yin Y, Wang R, Chen F, et al. Occurrence of high levels of cefiderocol resistance in carbapenem-resistant Escherichia coli before its approval in China: a report from China CRE-Network. Microbiol Spectr. 2022; 10 (3). doi: 10.1128/spectrum.02670-21.

39. Coppi M, Antonelli A, Niccolai C, Bartolini A, Bartolini L, Grazzini M, et al. Nosocomial outbreak by NDM-1-producing Klebsiella pneumoniae highly resistant to cefiderocol, Florence, Italy, August 2021 to June 2022. Euro Surveill. 2022; 27 (43): 2200795. doi: 10.2807/1560-7917.ES.2022.27.43.2200795.

40. Simner PJ, Beisken S, Bergman Y, Ante M, Posch AE, Tamma PD. Defining baseline mechanisms of cefiderocol resistance in the Enterobacterales. Microb Drug Resist. 2022; 28 (2): 161–170. doi: 10.1089/mdr.2021.0095.

41. Durand-Reville TF, Guler S, Comita-Prevoir J, Chen B, Bifuco N, Huynh H, et al. ETX2514 is a broad-spectrum β-lactamase inhibitor for the treatment of drug-resistant Gram-negative bacteria including Acinetobacter baumannii. Nat Microbiol. 2017; 2: 17104. doi: 10.1038/nmicrobiol.2017.104.

42. Shapiro AB. Kinetics of sulbactam hydrolysis by β-lactamases, and kinetics of β-lactamase inhibition by sulbactam. Antimicrob Agents Chemother. 2017; 61 (12): e01612–17. doi: 10.1128/AAC.01612-17.

43. Shapiro AB, Moussa SH, McLeod SM, Durand-Réville T, Miller AA. Durlobactam, a new diazabicyclooctane β-lactamase inhibitor for the treatment of Acinetobacter infections in combination with sulbactam. Front Microbiol. 2021; 12: 709974. doi: 10.3389/fmicb.2021.709974.

44. Bianco G, Gaibani P, Comini S, Boattini M, Banche G, Costa C, et al. Synergistic effect of clinically available β-lactamase inhibitors combined with cefiderocol against carbapenemase-producing Gram-negative organisms. Antibiotics (Basel). 2022; 11 (12): 1681. doi: 10.3390/antibiotics11121681.

45. Palombo M, Bovo F, Amadesi S, Gaibani P. Synergistic activity of cefiderocol in combination with piperacillin-tazobactam, fosfomycin, ampicillin-sulbactam, imipenem-relebactam and ceftazidime-avibactam against carbapenem-resistant Gram-negative bacteria. Antibiotics (Basel). 2023; 12 (5): 858. doi: 10.3390/antibiotics12050858.

46. Lewis RE, Palombo M, Diani E, Secci B, Gibellini D, Gaibani P. Synergistic activity of cefiderocol in combination with avibactam, sulbactam or tazobactam against carbapenem-resistant Gram-negative bacteria. Cells. 2024; 13 (16): 1315. doi: 10.3390/cells13161315.

47. Tumbarello M, Viale P, Viscoli C, Trecarichi EM, Tumietto F, Marchese A, et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy. Clin Infect Dis. 2012; 55 (7): 943–950. doi: 10.1093/cid/cis588.

48. Kazmierczak KM, Karlowsky JA, de Jonge BLM, Stone GG, Sahm DF. Epidemiology of carbapenem resistance determinants identified in meropenem-nonsusceptible Enterobacterales collected as part of a global surveillance program, 2012 to 2017. Antimicrob Agents Chemother. 2021; 65 (7): e0200020. doi: 10.1128/AAC.02000-20.

49. Kazmierczak KM, de Jonge BLM, Stone GG, Sahm DF. Longitudinal analysis of ESBL and carbapenemase carriage among Enterobacterales and Pseudomonas aeruginosa isolates collected in Europe as part of the International Network for Optimal Resistance Monitoring (INFORM) global surveillance programme, 2013-2017. J Antimicrob Chemother. 2020; 75 (5): 1165–1173. doi: 10.1093/jac/dkz571.

50. Nordmann P, Poirel L. Epidemiology and diagnostics of carbapenem resistance in Gram-negative bacteria. Clin Infect Dis. 2019; 69 (Suppl 7): S521–S528. doi: 10.1093/cid/ciz824.

51. Tamma PD, Goodman KE, Harris AD, Tekle T, Roberts A, Taiwo A, Simmer PJ. Comparing the outcomes of patients with carbapenemase-producing and non-carbapenemase-producing carbapenem-resistant Enterobacteriaceae bacteremia. Clin Infect Dis. 2017; 64 (3): 257–264. doi: 10.1093/cid/ciw741.

52. Hovan MR, Narayanan N, Cedarbaum V, Bhowmick T, Kirn TJ. Comparing mortality in patients with carbapenemase-producing carbapenem-resistant Enterobacterales and non-carbapenemase-producing carbapenem-resistant Enterobacterales bacteremia. Diagn Microbiol Infect Dis. 2021; 101 (4): 115505. doi: 10.1016/j.diagmicrobio.2021.115505.

53. Bush K, Jacoby GA. Updated functional classification of β-lactamases. Antimicrob Agents Chemother. 2010; 54 (3): 969–976. doi: 10.1128/AAC.01009-09.

54. Queenan AM, Bush K. Carbapenemases: the versatile β-lactamases. Clin Microbiol Rev. 2007;20(3):440-458. doi: 10.1128/CMR.00001-07.

55. Poirel L, Potron A, Nordmann P. OXA-48-like carbapenemases: the phantom menace. J Antimicrob Chemother. 2012; 6 7(7):1597–1606. doi: 10.1093/jac/dks121.

56. Jacoby GA. AmpC β-lactamases. Clin Microbiol Rev. 2009; 22 (1): 161–182. doi: 10.1128/CMR.00036-08.

57. Bonnin RA, Jousset AB, Emeraud C, Oueslati S, Dortet L, Naas T. Genetic diversity, biochemical properties, and detection methods of minor carbapenemases in Enterobacterales. Front Med (Lausanne). 2021; 7: 616490. doi: 10.3389/fmed.2020.616490.

58. Kazmierczak KM, Tsuji M, Wise MG, Haskel M, Yamano Y, Echols R, Sahm D,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. doi: 10.1016/j.ijantimicag.2018.10.007.

59. Takemura M, Kazmierczak KM, Hackel M, Sahm DF, Echols R, Yamano Y. In vitro activity of cefiderocol against metallo-β-lactamase-producing Gram-negative bacteria collected in North America and Europe between 2014 and 2017: SIDERO-WT-2014-2016 studies [abstract]. Open Forum Infect Dis. 2020; 7 (Suppl 1). doi: 10.1093/ofid/ofaa439.1436.

60. Longshaw C, Manissero D, Tsuji M, Echols R, Yamano Y. In vitro activity of the siderophore cephalosporin cefiderocol against molecularly characterized, carbapenem-non-susceptible Gram-negative bacteria from Europe. JAC Antimicrob Resist. 2020; 2 (3): dlaa060. doi: 10.1093/jacamr/dlaa060.

61. Oueslati S, Bogaerts P, Dortet L, Bernabeu S, Lakhal HB, Longshaw C, et al. In vitro activity of cefiderocol and comparators against carbapenem-resistant Gram-negative pathogens from France and Belgium. Antibiotics (Basel). 2022; 11 (10): 1352. doi: 10.3390/antibiotics11101352.

62. Bonnin RA, Emeraud C, Jousset AB, Naas T, Dortet L. Comparison of disk diffusion, MIC test strip and broth microdilution methods for cefiderocol susceptibility testing on carbapenem-resistant Enterobacterales. Clin Microbiol Infect. 2022; 28 (8): 1156.e1–1156.e5. doi: 10.1016/j.cmi.2022.04.013.

63. Timsit JF, Paul M, Shields RK, Echols R, Baba T, Yamano Y, Portsmouth S. Cefiderocol for the treatment of infections due to metallo-β-lactamase-producing pathogens in the CREDIBLE-CR and APEKS-NP phase 3 randomized studies. Clin Infect Dis. 2022; 75 (6): 1081–1084. doi: 10.1093/cid/ciac078.

64. 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. doi: 10.1093/cid/ciz826.

65. Ito A, Sato T, Ota M, Takemura M, Nishikawa T, Toba S, et al. In vitro antibacterial properties of cefiderocol, a novel siderophore cephalosporin, against Gram-negative bacteria. Antimicrob Agents Chemother. 2018; 62 (1): e01454–17. doi: 10.1128/AAC.01454-17.

66. Yamano Y. In vitro activity of cefiderocol against a broad range of clinically important Gram-negative bacteria. Clin Infect Dis. 2019; 69 (Suppl 7): S544–S551. doi: 10.1093/cid/ciz827.

67. Shortridge D, Streit JM, Mendes RE, Castanheira M. In vitro activity of cefiderocol against U.S. and European Gram-negative clinical isolates collected in 2020 as part of the SENTRY Antimicrobial Surveillance Program. Microbiol Spectr. 2022; 10 (2): e0271221. doi: 10.1128/spectrum.02712-21.

68. Karlowsky JA, Hackel MA, Takemura M, Yamano Y, Echols R, Sahm DF. In vitro susceptibility of Gram-negative pathogens to cefiderocol in five consecutive annual multinational SIDERO-WT surveillance studies, 2014 to 2019. Antimicrob Agents Chemother. 2022; 66 (2): e0199021. doi: 10.1128/AAC.01990-21.

69. Mushtaq S, Sadouki Z, Vickers A, Livermore DM, Woodford N. In vitro activity of cefiderocol, a siderophore cephalosporin, against multidrug-resistant Gram-negative bacteria. Antimicrob Agents Chemother. 2020; 64 (12): e01582–20. doi: 10.1128/AAC.01582-20.

70. European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. Version 16.0. Växjö: EUCAST; 2026.

71. European Committee on Antimicrobial Susceptibility Testing. Guidance document on broth microdilution testing of cefiderocol. Updated January 2024. Warnings concerning commercial antimicrobial susceptibility testing products: cefiderocol. Updated April 2025. Växjö: EUCAST; 2024-2025.

72. Gill CM, Santini D, Takemura M, Longshaw C, Yamano Y, Echols R, Nicolau D. In vivo efficacy and resistance prevention of cefiderocol in combination with ceftazidime-avibactam, ampicillin-sulbactam or meropenem using human-simulated regimens versus Acinetobacter baumannii. J Antimicrob Chemother. 2023; 78 (4): 983–990. doi: 10.1093/jac/dkad032.

73. Matsumoto S, Kanazawa S, Sato T, Yamano Y. Activities of cefiderocol with simulated human plasma concentrations against carbapenem-resistant Gram-negative bacilli in an in vitro chemostat model. Antimicrob Agents Chemother. 2020; 64 (11): e01128–20. doi: 10.1128/AAC.01128-20.

74. Longshaw C, Roger E, Santerre Henriksen A, Baba T, Nguyen S, Yamano Y. Evidence for efficacy of cefiderocol against OXA-48-containing isolates from the APEKS-NP and CREDIBLE-CR trials. Antimicrob Agents Chemother. 2022; 66 (10): e0110022. doi: 10.1128/AAC.01100-22.

75. Choby JE, Ozturk T, Satola SW, Jacob JT, Weiss DS. Widespread cefiderocol heteroresistance in carbapenem-resistant Gram-negative pathogens. Lancet Infect Dis. 2021; 21 (5): 597–598. doi: 10.1016/S1473-3099(21)00194-8.

76. Kobic E, Abouelhassan Y, Singaravelu K, Nicolau DP. Pharmacokinetic analysis and in vitro synergy evaluation of cefiderocol, sulbactam, and tigecycline in an extensively drug-resistant Acinetobacter baumannii pneumonia patient receiving continuous venovenous hemodiafiltration. Open Forum Infect Dis. 2022; 9 (10): ofac484. doi: 10.1093/ofid/ofac484.

77. Halim J, Keane AP, Bouzo J, Aderibigbe T, Chicola JA, Nolan KT, et al. Synergistic cefiderocol-containing antibiotic combinations active against highly drug-resistant Acinetobacter baumannii patient isolates with diverse resistance mechanisms. J Antimicrob Chemother. 2025; 80 (10): 2814–2824. doi: 10.1093/jac/dkaf306.

78. Monogue ML, Tsuji M, Yamano Y, Echols R, Nicolau DP. Efficacy of humanized exposures of cefiderocol (S-649266) against a diverse population of Gram-negative bacteria in a murine thigh infection model. Antimicrob Agents Chemother. 2017; 61 (11): e01022-17. doi: 10.1128/AAC.01022-17.

79. Nakamura R, Ito-Horiyama T, Takemura M, Toba M, Matsumoto S, Ikehara T, et al. In vivo pharmacodynamic study of cefiderocol, a novel parenteral siderophore cephalosporin, in murine thigh and lung infection models. Antimicrob Agents Chemother. 2019; 63 (9): e02031-18. doi: 10.1128/AAC.02031-18.

80. Matsumoto S, Singley CM, Hoover J, Nakamura R, Echols R, Rittenhouse S, et al. Efficacy of cefiderocol against carbapenem-resistant Gram-negative bacilli in immunocompetent-rat respiratory tract infection models recreating human plasma pharmacokinetics. Antimicrob Agents Chemother. 2017; 61 (9): e00700-17. doi: 10.1128/AAC.00700-17.

81. Katsube T, Wajima T, Ishibashi T, Arjona Ferreira JC, Echols R. Pharmacokinetic/pharmacodynamic modeling and simulation of cefiderocol, a parenteral siderophore cephalosporin, for dose adjustment based on renal function. Antimicrob Agents Chemother. 2017; 61 (1): e01381-16. doi: 10.1128/AAC.01381-16.

82. Kawaguchi N, Katsube T, Echols R, Wajima T. Population pharmacokinetic and pharmacokinetic/pharmacodynamic analyses of cefiderocol, a parenteral siderophore cephalosporin, in patients with pneumonia, bloodstream infection/sepsis, or complicated urinary tract infection. Antimicrob Agents Chemother. 2021; 65 (3): e01437-20. doi: 10.1128/AAC.01437-20.

83. Wenzler E, Butler D, Tan X, Katsube T, Wajima T. Pharmacokinetics, pharmacodynamics, and dose optimization of cefiderocol during continuous renal replacement therapy. Clin Pharmacokinet. 2022; 61 (4): 539–552. doi: 10.1007/s40262-021-01086-y.

84. Kawaguchi N, Katsube T, Echols R, Wajima T, Nicolau DP. Intrapulmonary pharmacokinetic modeling and simulation of cefiderocol, a parenteral siderophore cephalosporin, in patients with pneumonia and healthy subjects. J Clin Pharmacol. 2022; 62 (5): 670–680. doi: 10.1002/jcph.1986.

85. Portsmouth S, van Veenhuyzen D, Echols R, Machida M, Ferreira JCA, Ariyasu M, et al. Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2018; 18 (12): 1319–1328. doi: 10.1016/S1473-3099(18)30554-1.

86. Wunderink RG, Matsunaga Y, Ariyasu M, Clevenbergh P, Echols R, Kaye K, et al. Cefiderocol versus high-dose, extended-infusion meropenem for the treatment of Gram-negative nosocomial pneumonia (APEKS-NP): a randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis. 2021 ;21 (2): 213–225. doi: 10.1016/S1473-3099(20)30731-3.

87. Bassetti M, Echols R, Matsunaga Y, Ariyasu M, Doi Y, Ferrer R, et al. Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial. Lancet Infect Dis. 2021; 21 (2): 226–240. doi: 10.1016/S1473-3099(20)30796-9.

88. Paterson DL, Kinoshita M, Baba T, Echols R, Portsmouth S. Outcomes with cefiderocol treatment in patients with bacteraemia enrolled into prospective phase 2 and phase 3 randomised clinical studies. Infect Dis Ther. 2022; 11 (2): 853–870. doi: 10.1007/s40121-022-00598-9.

89. Lampejo T, Cherian BP, Tan MGM, Wareham DW. Cefiderocol in the treatment of systemic carbapenemase-producing multidrug-resistant Klebsiella pneumoniae infection. J Glob Antimicrob Resist. 2020; 23: 338–339. doi: 10.1016/j.jgar.2020.10.008.

90. Bleibtreu A, Dortet L, Bonnin RA, et al.; Cefiderocol French Study Group. Susceptibility testing is key for the success of cefiderocol treatment: a retrospective cohort study. Microorganisms. 2021;9(2):282. DOI: 10.3390/microorganisms9020282.

91. Colombo F, Waheed A, Panese S, Scarparo C, Solinas M, Parisi SG, Geremia N. Treatment with cefiderocol in K. pneumoniae KPC nosocomial external ventricular drainage meningitis: a brief report. Infez Med. 2022; 30 (3): 454–458. doi: 10.53854/liim-3003-15.

92. Monari C, Spagnuolo F, Pisaturo M, Ascione S, Donnarumma G, Calò F, et al. Bloodstream infection due to a VIM-metallo-β-lactamase-producing Klebsiella pneumoniae treated with cefiderocol in a preterm newborn. Infect Dis Ther. 2023; 12 (2): 727–734. doi: 10.1007/s40121-022-00735-4.