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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.
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    Antibacterial Prodrugs to Overcome Bacterial Resistance

    molecules Review Antibacterial Prodrugs to Overcome Bacterial Resistance Buthaina Jubeh , Zeinab Breijyeh and Rafik Karaman * Pharmaceutical Sciences Department, Faculty of Pharmacy, Al-Quds University, Jerusalem P.O. Box 20002, Palestine; [email protected] (B.J.); [email protected] (Z.B.) * Correspondence: [email protected] or rkaraman@staff.alquds.edu Academic Editor: Helen Osborn Received: 10 March 2020; Accepted: 26 March 2020; Published: 28 March 2020 Abstract: Bacterial resistance to present antibiotics is emerging at a high pace that makes the development of new treatments a must. At the same time, the development of novel antibiotics for resistant bacteria is a slow-paced process. Amid the massive need for new drug treatments to combat resistance, time and effort preserving approaches, like the prodrug approach, are most needed. Prodrugs are pharmacologically inactive entities of active drugs that undergo biotransformation before eliciting their pharmacological effects. A prodrug strategy can be used to revive drugs discarded due to a lack of appropriate pharmacokinetic and drug-like properties, or high host toxicity. A special advantage of the use of the prodrug approach in the era of bacterial resistance is targeting resistant bacteria by developing prodrugs that require bacterium-specific enzymes to release the active drug. In this article, we review the up-to-date implementation of prodrugs to develop medications that are active against drug-resistant bacteria. Keywords: prodrugs; biotransformation; targeting; β-lactam antibiotics; β-lactamases; pathogens; resistance 1. Introduction Nowadays, the issue of pathogens resistant to drugs and the urgent need for new compounds that are capable of eradicating these pathogens are well known and understood.