P1314 Surveillance of Cefiderocol In Vitro Activity against Gram-Negative Clinical Isolates Collected Contact Information : Masakatsu Tsuji in Europe: SIDERO-WT-2014 Address: 3-1-1, Futaba-cho, Toyonaka, Osaka, 561-0825, JAPAN TEL: +81-6-6331-8272 27th ECCMID 1) 2) 1) 3) 2) FAX: +81-6-6331-8612 Masakatsu Tsuji , Meredith Hackel , Yoshinori Yamano , Roger Echols and Daniel F Sahm E-mail address: [email protected] Vienna, Austria 22-25 April, 2017 1) Shionogi & Co., Ltd., Osaka JP, 2) IHMA, Inc. Schaumburg, IL, US, 3) ID3C, LLC, Easton CT, US

Compound testing cefiderocol, iron-deficient cation-adjusted Muller-Hinton Broth ABSTRACT Cefiderocol, cefepime, ceftazidime-avibactam, ceftolozane-tazobactam, (ID-CAMHB) was used according to CLSI approved guidelines (3, 4). The RESULTS Background: ciprofloxacin, colistin and meropenem were used. cefiderocol MIC was read as the first drug well in which the growth was significantly reduced (i.e. a button of < 1 mm or light/faint turbidity) relative • Cefiderocol MIC50 and MIC90 values were the lowest of all compounds tested (Table 2, Figure 3-5). Figure 4. Cumulative percentage of cefiderocol MIC against 570 carbapenem- The emergence and dissemination of potent resistance mechanisms among Gram-negative bacterial Antimicrobial Susceptibility Testing to the growth observed in the growth control. Escherichia coli ATCC 25922 • The cefiderocol MIC90 value was 1 mg/L for all Enterobacteriaceae and 4 mg/L for resistant A. baumanii from EU. species underscores the need for the development of new and effective therapeutic choices to treat Antimicrobial susceptibility testing was done using broth microdilution meropenem-resistant Enterobacteriaceae. Of these meropenem resistant isolates, 3072 and Pseudomonas aeruginosa ATCC 27853 were used as the CLSI reference 100 the infections caused by these challenging organisms. Cefiderocol (formerly S-649266) is a novel Cefiderocol methods according to Clinical and Laboratories Standard Institute. For quality control (QC) strains. isolates (99.7 %) of the all isolates exhibited cefiderocol MIC values of ≤4 mg/L. Cefepime 90 Ceftazidime-avibactam parenteral siderophore cephalosporin with potent activity against a wide variety of Gram-negative • The cefiderocol MIC90 values were 0.5 mg/L for all P. aeruginosa and 1 mg/L for Ceftolozane-tazobactam 80 pathogens including carbapenem-resistant strains. This study evaluated the in vitro activity of Ciprofloxacin

meropenem-resistant P. aeruginosa. All isolates exhibited cefiderocol MIC values of ≤4 mg/L. (% ) Colistin Table 1. Distribution of isolates tested by country Table 3. Summary of resistant percentage among European isolates e cefiderocol and comparator agents against recent clinical isolates collected in 2014-2015 from Europe. g 70

• The cefiderocol MIC90 value was 1 mg/L for all A. baumannii, including a Meropenem t

meropenem-resistant A. baumannii. Eight hundred thirty-three isolates (99.2 %) of the all e n 60 Region Country N % of Total Organism Cefiderocol % S Colistin % S CPFX % S Ceftolozane-tazobactam % S MIC Ceftazidime-avi c

Materials and methods: e r

MIC ≤4 mg/L MIC ≤1 mg/L MIC ≤1 mg/L ≤4 mg/L for non-fermenters; bactam % S p isolates exhibited cefiderocol MIC values of ≤4 mg/L. 50 Czech Republic 444 8.9 ≤2 mg/L for Enterobacteriaceae MIC ≤8 mg/L e A total of 3080 Enterobacteriaceae, 839 Acinetobacter baumannii, 765 Pseudomonas aeruginosa, v

• The cefiderocol MIC90 value was 0.25 mg/L for all S. malthophilia. Other comparator ti 276 Stenotrophomonas maltophilia, and 6 Burkholderia cepacia collected from 11 European France 484 9.7 All Gram-negative 40 (N=4966) 99.3 85.0 61.2 73.9 85.4 compounds only demonstrated minimal if any activity. m ul a countries in 2014 - 2015 were tested. MICs were determined for cefiderocol, cefepime (FEP), Enterobacteriaceae 30 Germany 602 12.1 C u (N=3080) 99.7 82.0 76.3 85.2 98.6 ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C/T), ciprofloxacin (CIP), colistin (CST), and 20 Greece 502 10.1 Non-fermenters Figure 1.Cefiderocol MIC distribution of 4966 Gram-negative bacteria from EU. meropenem (MEM) by broth microdilution and interpreted according to CLSI 2016 guidelines. (N=1886) 98.7 89.0 36.6 55.6 63.9 Hungary 359 7.2 10 CarbNS 30 Cefiderocol was tested in iron-depleted cation-adjusted Mueller Hinton broth as approved by CLSI. Enterobactereaceae (3080) Europe Enterobacteriaceae 96.0 69.6 6.4 5.6 71.2 0 Italy P. aeruginosa (765) 679 13.7 ≦0.004 0.008 0.016 0.031 0.063 0.125 0.25 0.5 1 2 4 8 16 32 64 >64 Carbapenem-resistant (CR) isolates were defined using EUCAST breakpoints of MEM (resistant, >8 (N=125) A. baumannii (839) mg/L). EUCAST MIC breakpoints for CZA (resistant, >8 mg/L) and C/T (resistant, >1 mg/L) were used. Russia 345 6.9 CarbNS non- S. malthopilia (276) Drug concentration (mg/L) fermenters 98.0 83.6 5.3 25.1 39.1 25 For colistin, EUCAST MIC breakpoints for Enterobacteriaceae were applied (resistant, >2 mg/L). Spain 460 9.3 (N=1070) CarbNS P. aeruginosa ) Figure 5. Cumulative percent cefiderocol MIC of 276 against S. malthophilia. Quality control testing was performed on each day of testing. Breakpoints to cefiderocol have not Sweden 164 3.3 100 99.0 21.8 67.3 68.3

(N=202) ( % been established, however, in vivo PK/PD infection models using human drug exposures suggest 20 100 CarbNS A. baumannii e s Cefiderocol Turkey 527 10.6 96.5 82.7 0.2 5.0 25.4 t a Cefepime efficacy when MICs to cefiderocol are < 8 mg/L. (N=570) 90 United Kingdom 400 8.1 S. malthophilia ol Ceftazidime-avibactam

100 73.9 4.3 38.4 48.9 i s (N=276) 15 80 Ceftolozane-tazobactam o f Results: Total 4966 100 ) Ciprofloxacin e Note: Non-fermenters includes P. aeruginosa, A. baumannii, S. maltophilia, B. cepacia % Colistin ( g 70 a e Meropenem

As shown in the following table, cefiderocol exhibited potent in vitro activity against 4966 strains of t

10 ta g 60

Gram-negative bacteria with MIC90 of 1 mg/L. MIC90 of cefiderocol against P. aeruginosa, A. ce n e n c e r r 50 e baumannii, S. maltophilia and Enterobacteriaceae including the subset of CR or CZA resistant Table 2. P p e

isolates were 4 mg/L or less. Cefiderocol inhibited the growth of 99.3% of all the isolates at 4 mg/L v 5 40 a ti or less. 14.8%, 29.3% and 15.0% of all the isolates showed resistance to CZA, C/T and CST, l MIC (mg/L) MIC (mg/L) u 30 respectively. Species (number of isolates) Test compound Species (number of isolates) Test compound m Range 50% 90% Range 50% 90% C u 20 0 Escherichia coli Cefiderocol ≤0.03 — 4 0.12 0.5 Serratia marcescens Cefiderocol ≤0.03 — 8 0.12 0.5 0.002 0.004 0.008 0.015 0.031 0.063 0.125 0.25 0.5 1 2 4 8 16 32 64 Conclusions: (789) Cefepime 0.06 — 64 0.06 64 (455) Cefepime 0.06 — 64 0.12 0.5 Cefiderocol MIC (mg/L) 10 Ceftazidime-avibactam 0.06 — 32 0.12 0.25 Ceftazidime-avibactam 0.06 — 64 0.12 0.5 The potent in vitro activity that cefiderocol demonstrated against CR A. baumannii, CR P. Ceftolozane-Tazobactam 0.06 — 64 0.12 0.5 Ceftolozane-tazobactam 0.25 — 64 0.5 1 0 Figure 2.Cefiderocol MIC distribution of 1173 Meropenem non-susceptible Gram-negative ≦0.004 0.008 0.016 0.031 0.063 0.125 0.25 0.5 1 2 4 8 16 32 64 >64 aeruginosa, and CR Enterobacteriaceae isolates collected from Europe, with greater than 99.3% of Ciprofloxacin 0.12 — 8 0.12 8 Ciprofloxacin 0.12 — 8 0.12 1 Colistin 0.25 — 8 0.5 1 Colistin 0.5 — 8 >8 >8 bacteria from EU. Drug concentration (μg/mL) isolates having MIC values ≤4 mg/L, indicates this agent has high potential for treating infections Meropenem 0.06 — 4 0.06 0.06 Meropenem 0.06 — 64 0.06 0.12 Klebsiella pneumoniae — Pseudomonas aeruginosa Cefiderocol ≤0.03 — 4 0.12 0.5 30 Enterobactereaceae (125) caused by these problematic organisms. Cefiderocol ≤0.03 8 0.12 2 P. aeruginosa (202) (761) Cefepime 0.06 — 64 0.12 64 (765) Cefepime 0.06 — 64 4 32 A. baumannii (570) Ceftazidime-avibactam 0.06 — 65 0.25 1 Ceftazidime-avibactam 0.06 — 64 2 8 S. malthopilia (276) MIC (mg/L) — Ceftolozane-tazobactam 0.06 — 64 0.5 4 90 Ceftolozane-Tazobactam 0.06 65 0.5 64 25 CONCLUSIONS Organisms Ciprofloxacin 0.12 — 8 0.12 >8 Ciprofloxacin 0.12 — 8 0.25 8

N Cefiderocol FEP CZA C/T CIP CST MEM Colistin 0.25 — 8 0.5 1 Colistin 0.25 — 8 1 2 ) Meropenem 0.06 — 64 0.06 8 Meropenem 0.06 — 64 0.5 16 • Cefiderocol demonstrated potent in vitro against Enterobacteriaceae, A. baumannii, Klebsiella pneumoniae Cefiderocol 0.25 — 16 2 4 Pseudomonas aeruginosa Cefiderocol ≤0.03 — 4 0.5 2 ( % 20

E. coli 789 0.5 64 0.25 0.5 8 1 0.06 e s CZA resistant strain (22) Cefepime 16 — 64 64 64 CZA resistant strain (64) Cefepime 1 — 64 64 64 t P. aeruginosa, and S. maltophilia including carbapenem resistant isolates collected from (>8 mg/L) Ceftazidime-avibactam 16 — 64 64 64 (>16 mg/L) Ceftazidime-avibactam 16 — 64 32 32 K. pneumoniae 761 2 64 1 64 >8 1 8 ol a Europe. — Ceftolozane-tazobactam 1 — 64 64 64

Ceftolozane-tazobactam 0.5 64 64 64 i s CZA-resistant K. pneumoniae 22 4 64 64 64 >8 >8 64 Ciprofloxacin 0.5 — 8 >8 >8 15 Ciprofloxacin 0.12 — 8 >8 >8 o f • Cefiderocol also displayed a high degree of activity against many Gram-negative bacteria

Colistin 0.25 — 8 0.5 >8 Colistin 0.25 — 4 1 1 e CR K. pneumoniae 74 4 64 64 64 >8 1 32 g resistant to newer agents such as ceftazidime-avibactam and ceftolozane-tazobactam Meropenem 0.06 — 64 32 64 Meropenem 4 — 64 32 64 a t

Klebsiella pneumoniae Cefiderocol ≤0.03 — 8 1 4 Pseudomonas aeruginosa Cefiderocol ≤0.03 — 4 0.25 2 n resistant P. aeruginosa. P. aeruginosa 765 0.5 32 8 4 8 2 16 10 MEM resistant strains(74) Cefepime 16 — 64 64 64 C/T resistant strains (70) Cefepime 4 — 64 32 64 ce r

C/T resistant P. aeruginosa 70 2 64 64 64 8 8 64 (>8 mg/L) Ceftazidime-avibactam 0.25 — 64 8 64 (>8 mg/L) Ceftazidime-avibactam 1 — 64 32 64 e • Cefiderocol is a promising new siderophore cephalosporin for the treatment of Ceftolozane-tazobactam 1 — 64 64 64 Ceftolozane-tazobactam 8 — 64 64 64 P infections caused by a variety of highly resistant Gram-negative pathogens. CR P. aeruginosa 83 1 64 64 64 8 1 64 — Ciprofloxacin 0.12 — 8 8 8 Ciprofloxacin 0.12 8 >8 >8 5 — Colistin 0.25 — 4 4 8 A. baumannii 839 1 64 64 64 >8 8 64 Colistin 0.25 8 0.5 1 Meropenem 4 — 64 8 32 Meropenem 0.12 — 64 32 64 CR A. baumannii 570 1 64 64 64 8 8 64 Klebsiella oxytoca Cefiderocol ≤0.03 — 2 0.029 0.25 Pseudomonas aeruginosa Cefiderocol ≤0.03 — 64 0.25 1 REFERENCES (260) Cefepime 0.06 — 64 0.06 1 MEM resistant strains (83) Cefepime 1 — 64 16 64 0 S. malthophilia 276 0.25 64 32 64 8 8 64 Ceftazidime-avibactam 0.06 — 64 0.12 0.25 (>16 mg/L) Ceftazidime-avibactam 1 — 64 8 64 0.002 0.004 0.008 0.015 0.031 0.063 0.125 0.25 0.5 1 2 4 8 16 32 64 Ceftolozane-tazobactam 0.12 — 64 0.25 0.5 Ceftolozane-tazobactam 0.5 — 64 2 64 Cefiderocol MIC (mg/L) 1. T. Horiyama, Y. Ishii, A, Ito, T. Sato, R. Nakamura, N. Fukuhara, M. Tsuji, Y. Yamano, K. Ciprofloxacin 0.12 — 8 0.12 0.12 Ciprofloxacin 0.12 — 8 8 8 Colistin 0.25 — 2 0.5 1 Colistin 0.25 — 4 1 1 Figure 3. Cumulative percentage of cefiderocol MIC against 70 ceftoloane-tazobactam resistant Yamaguchi, and K. Tateda. Stability of Novel Siderophore Cephalosporin S-649266 INTRODUCTION Meropenem 0.06 — 8 0.06 0.06 Meropenem 8 — 64 16 64 against Clinically Relevant Carbapenemases: AAC 2016 July 60(7):4383-86. Citrobacter freundii Cefiderocol ≤0.03 — 2 0.12 0.5 Acinetobacter baumannii Cefiderocol ≤0.03 — 64 0.12 1 P. aeruginosa from EU. (160) Cefepime 0.06 — 64 0.06 2 (839) Cefepime 0.06 — 64 64 64 100 2. A, Ito, T. Nishikawa, S. Matsumoto, H. Yoshizawa, T. Sato, R. Nakamura, M. Tsuji, and Y. Cefiderocol (S-649266) is a novel parenteral catechol-substituted siderophore cephalosporin that Cefiderocol Ceftazidime-avibactam 0.06 — 64 0.12 0.5 Ceftazidime-avibactam 0.06 — 64 16 64 Cefepime 90 Yamano Siderophore Cephalosporin Cefiderocol Utilizes Ferric Iron Transporter Systems is active against carbapenem-resistant Gram-negative bacteria (1, 2). In this study, we evaluated Ceftolozane-tazobactam 0.12 — 64 0.25 16 Ceftolozane-tazobactam 0.06 — 64 8 64 Ceftazidime-avibactam Ciprofloxacin 0.12 — 8 0.12 4 Ciprofloxacin 0.12 — 8 >8 >8 Ceftolozane-tazobactam for Antibacterial Activity against Pseudomonas aeruginosa. AAC 2016 November the in vitro activity of cefiderocol and comparators against Gram-negative bacteria collected from 80 Colistin 0.25 — 2 0.5 1 Colistin 0.25 — 8 1 8 Ciprofloxacin 60(12):7396-7401. — Meropenem 0.06 — 64 32 64 Colistin patients throughout Europe. Meropenem 0.06 8 0.06 0.12 70 Enterobacter aerogenes Cefiderocol ≤0.03 — 8 0.12 0.5 Acinetobacter baumannii Cefiderocol ≤0.03 — 64 0.12 1 Meropenem 3. Clinical Laboratory Standards Institute (CLSI), 2015. Methods for Dilution Antimicrobial (204) Cefepime 0.06 — 64 0.06 1 MEM resistant strains (83) Cefepime 4 — 64 64 64 60 Ceftazidime-avibactam 0.06 — 8 0.25 0.5 (>16 mg/L) Ceftazidime-avibactam 1 — 64 32 64 Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standards -- Tenth MATERIALS AND METHODS Ceftolozane-tazobactam 0.12 — 32 0.5 4 Ceftolozane-tazobactam 1 — 64 16 64 50 Edition. CLSI document M07-A10 (ISBN 1-56238-988-2). CLSI, 940 West Valley Road, Ciprofloxacin 0.12 — 8 0.12 0.25 Ciprofloxacin 0.12 — 8 8 8 Colistin 0.25 — 8 0.5 1 Colistin 0.25 — 8 1 8 40 Suite 1400, Wayne, Pennsylvania 19087-1898 USA. Meropenem 0.06 — 64 0.06 0.12 Meropenem 8 — 64 64 64 Test organisms 30 4. Clinical and Laboratory Standards Institute (CLSI), 2015. Performance Standards for Enterobacter cloacae Cefiderocol ≤0.03 — 64 0.25 1 Stenotrophomonas maltophilia Cefiderocol ≤0.03 — 2 0.06 0.25 In all 4,966 clinical isolates of Gram-negative bacilli from 11 European countries in 2014 - 2015 — (276) Cefepime 0.5 — 64 32 64 Antimicrobial Susceptibility Testing; Twenty-Fifth Informational Supplement. CLSI (301) Cefepime 0.06 4 0.12 32 Cumulative percentage (%) 20 were analyzed. All isolates were sent to a central laboratories, International Health Management Ceftazidime-avibactam 0.06 — 64 0.25 1 Ceftazidime-avibactam 0.5 — 64 16 32 Document M100-S25 (ISBN 1-56238-990-4). CLSI, 940 West Valley Road, Ceftolozane-tazobactam 0.12 — 64 0.5 16 Ceftolozane-tazobactam 0.12 — 64 8 64 10 Associates, Inc (IHMA) in Schaumburg, Illinois where the isolates were further evaluated and Ciprofloxacin 0.12 — 8 0.12 8 Ciprofloxacin 0.12 — 8 2 8 Suite 1400, Wayne, Pennsylvania 19087-1898 USA. stored. Among 9205 strains collected from SIDERO-WT-2014 study, strains isolated from Europe Colistin 0.25 — 8 0.5 1 Colistin 0.25 — 8 1 8 0 Meropenem 0.06 — 64 0.06 0.25 Meropenem 0.12 — 64 64 64 ≦0.004 0.008 0.016 0.031 0.063 0.125 0.25 0.5 1 2 4 8 16 32 64 >64 were tested. Table 2 shows the region information of test strains which were used for in vitro Drug concentration (mg/L) studies. http://www.shionogi.co.jp/publication/mbix6fdd8.pdf