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 n meropenem-resistant A. baumannii. Eight hundred thirty-three isolates (99.2 %) of the all e 60 Organism c Region Country N % of Total Cefiderocol % S Colistin % S CPFX % S Ceftolozane-tazobactam % S MIC Ceftazidime-avi r Materials and methods: e 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 All Gram-negative a 40 France 484 9.7 ul (N=4966) 99.3 85.0 61.2 73.9 85.4 compounds only demonstrated minimal if any activity. m countries in 2014 - 2015 were tested. MICs were determined for cefiderocol, cefepime (FEP), Enterobacteriaceae u 30 Germany 602 12.1 C (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 s 20 100 CarbNS A. baumannii e 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 ol Ceftazidime-avibactam United Kingdom 400 8.1 S. malthophilia s 100 73.9 4.3 38.4 48.9 i Ceftolozane-tazobactam (N=276) f 15 80 o ) 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 g n 10 ta 60 n Gram-negative bacteria with MIC90 of 1 mg/L. MIC90 of cefiderocol against P. aeruginosa, A. ce e r c e 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 ti a 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 Species (number of isolates) Test compound Species (number of isolates) Test compound m respectively. u Range 50% 90% Range 50% 90% C 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, Pseudomonas aeruginosa Klebsiella pneumoniae Cefiderocol 0.25 — 16 2 4 Cefiderocol ≤0.03 — 4 0.5 2 s 20 E. coli 789 0.5 64 0.25 0.5 8 1 0.06 e 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 a K. pneumoniae 761 2 64 1 64 >8 1 8 ol Europe.