Activity of the novel siderophore cephalosporin cefiderocol against multidrug-resistant Gram-negative pathogens

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1 Published in "Europen Journl of Clinicl Microbiology & Infectious Diseses doi: /s z, 2017" which should be cited to refer to this work. Activity of the novel siderophore cephlosporin cefiderocol ginst multidrug-resistnt Grm-negtive pthogens J. Dobis 1,2,3,4 & V. Dénervud-Tendon 1,2,3,4 & L. Poirel 1,2,3,4 & P. Nordmnn 1,2,3,4,5 Abstrct The novel siderophore cephlosporin cefiderocol (S ) with potent ctivity ginst Grm-negtive pthogens ws recently developed (Shionogi & Co., Ltd.). Here, we evluted the ctivity of this new molecule nd comprtors ginst collection of previously chrcterized Grm-negtive isoltes using broth microdilution pnels. A totl of 753 clinicl multidrug-resistnt Grm-negtive isoltes collected from hospitls worldwide were tested ginst cefiderocol nd ntibiotic comprtors (ceftolozne tzobctm [CT], meropenem [MEM], ceftzidime [CAZ], ceftzidime vibctm [CZA], colistin [CST], ztreonm [ATM], mikcin [AMK], ciprofloxcin [CIP], cefepime [FEP], nd tigecycline [TGC]) for their susceptibility. The collection included Escherichi coli (n = 164), Klebsiell pneumonie (n = 298), Enterobcter sp. (n = 159), Pseudomons eruginos (n = 45), nd Acinetobcter bumnnii (n = 87). Resistnce mechnisms included producers of crbpenemses nd extended-spectrum β-lctmses (ESBLs). In ddition, series of colistinresistnt enterobcteril isoltes (n = 74), including 15 MCR- 1 producers, were tested. The of cefiderocol ws 2 mg/ * P. Nordmnn ptrice.nordmnn@unifr.ch Emerging Antibiotic Resistnce Unit, University of Fribourg, Fribourg, Switzerlnd Ntionl Reference Center for Emerging Antibiotic Resistnce (Switzerlnd), University of Fribourg, Fribourg, Switzerlnd French INSERM Europen Unit (LEA/IAME), University of Fribourg, Fribourg, Switzerlnd Medicl nd Moleculr Microbiology Unit, Deprtment of Medicine, University of Fribourg, rue Albert Gockel 3, 1700 Fribourg, Switzerlnd Institute for Microbiology, University of Lusnne nd University Hospitl Centre, Lusnne, Switzerlnd L, while those of comprtive drugs were >64 mg/l for CT, MEM, CAZ, CZA, nd AMK, >32 mg/l for ATM, >16 mg/l for FEP, 8 mg/l for CST, nd 2 mg/l for TGC. The MIC 50 of cefiderocol ws 0.5 mg/l, while those of other drugs were >64 mg/l for CAZ, 64 mg/l for CT, >32 mg/l for ATM, >16 mg/l for FEP, 8 mg/l for MEM nd AMK, >4 mg/l for CIP, 1 mg/l for CZA, 0.5 mg/l for TGC, nd <0.5 mg/l for CST. Only 20 out of 753 strins showed MIC vlues of cefiderocol 8 μg/ml. Compred to the other drugs tested, cefiderocol ws more ctive, with the exception of colistin nd tigecycline showing equivlent ctivity ginst certin subgroups of bcteri. Introduction Grm-negtive bcteri tht produce extended-spectrum β- lctmses (ESBLs) re mjor concern in helthcre due to their bility to spred globlly [1]. ESBLs re mjor group of enzymes tht confer resistnce to severl genertions of β- lctm ntibiotics, including third-genertion cephlosporins [2, 3]. ESBL-encoding genes tht re primrily plsmidencoded include mostly TEM-, SHV-, nd CTX-M-type enzymes [4]. Enterobctericee, such s Klebsiell pneumonie nd Escherichi coli, re the min ESBL producers tht hve been reported globlly. Crbpenems re mostly used for the tretment of infections due to ESBL-producing bcteri, but crbpenemse-producing bcteri re now extensively reported [5, 6]. Polymyxins (e.g., colistin nd polymyxin B) re now more frequently used s lst-resort ntibiotics for treting ptients with multidrug-resistnt bcteril infections [7]. However, recent report shows tht novel gene (mcr-1) s source of plsmid-encoded resistnce encoded on plsmid in E. coli my quickly spred to other bcteril strins or species [8 10]. Therefore, due to the incresing thret of 1

2 multidrug-resistnt nd pndrug-resistnt bcteri, there is need for novel molecules. Cefiderocol (CFDC) is novel prenterl siderophore cephlosporin lso known s S It possesses unique mechnism for penetrting efficiently into Grm-negtive pthogens. It uses BTrojn horse^ strtegy by binding free iron nd is then ctively trnsported into bcteril cells cross the outer membrne of Grm-negtive bcteri by wy of the iron-trnsport system [11, 12]. Cefiderocol is cephlosporin molecule with n ttched ctechol moiety on the 3-position side chin which binds to ferric iron [11]. Once cross the outer membrne, the iron dissocites nd the cephlosporin binds to penicillin-binding proteins (PBP), minly PBP3, s other cephlosporins do to disrupt cell wll synthesis [11, 13], contributing to potent ntimicrobil ctivity ginst Grm-negtive bcteri. In ddition, this ntimicrobil ctivity of cefiderocol is enhnced by the high stbility of cefiderocol to hydrolysis by nerly ll β-lctmses, including both the serine nd metllo-crbpenemses [14]. The bility to cross the outer membrne through the ctive iron-trnsport system overcomes resistnce due to porin chnnel muttions nd efflux pump overproducers. It results tht cefiderocol exhibits potent in vitro nd in vivo ctivity ginst ll species of Grmnegtive bcteri, including crbpenem-resistnt strins of Enterobctericee, Pseudomons eruginos, nd Acinetobcter bumnnii, nd even Stenotrophomons mltophili [15]. Here, we evluted the ntimicrobil ctivity of cefiderocol nd other Grm-negtive ntibiotics (ztreonm, mikcin, cefepime, ceftzidime, ceftzidime vibctm, ceftolozne tzobctm, ciprofloxcin, meropenem, colistin, nd tigecycline) ginst pnel of 753 multidrug-resistnt bcteril isoltes from humn clinicl sources with chrcterized ntibiotic resistnce mechnisms. Mterils nd methods Bcteril isoltes A totl of 753 clinicl multidrug-resistnt isoltes were evluted in this study (Tble 1). They were representtive of the most widespred nd brod-spectrum mechnisms of resistnce currently observed worldwide in Grm-negtive bcteri. The strins were collected from hospitls worldwide (42 countries) from 2000 to 2016, with mjority dting from the period. They were of vrious origins (not lwys recorded) but mostly from urines, broncho-lveolr specimens, blood, pus, nd stools. In vitro susceptibility test methods Minimum inhibitory concentrtions (MICs) were determined following the Clinicl nd Lbortory Stndrds Institute (CLSI) broth microdilution (BMD) guidelines [16]. Frozen Tble 1 Genus (species) Bcteril strins tested in this study Number of tested isoltes Chrcterized resistnce Escherichi coli (164) 43 OXA (-1/48/181/204) 22 VIM (-1/2/4/19), IMP (-1/8) 45 NDM (-1/4/5/6/7) 11 KPC (-2/3) 25 CTX-M (-1/3/15) 15 MCR-1 3 Non-MCR-1 colistin resistnt Klebsiell pneumonie (298) 101 KPC (-2/3/11) 89 OXA (-48/162/163/181/204/232) 18 NDM b (-1/4) 20 VIM (-1/4/19), IMP (-1/4/8) 25 CTX-M (-3/15) 45 Colistin R Enterobctericee (159) 26 OXA (-48/163) 10 NDM-1 5 VIM-1 14 IMP (-1/8) 14 KPC-2 49 CTX-M (-3/15) 7 VEB-1 14 SHV-12 9 Plsmid-medited AmpC nd overproducer of AmpC 11 Colistin R Pseudomons eruginos (45) 6 PER-1 9 SHV (-2/5/12), GES (-1/9) 20 IMP (-1/2/10/13/15/19/29), KPC-2 10 VIM (-1/2), SPM-1, GIM-1 Acinetobcter bumnnii (87) 85 OXA-23/40/58/72 2 NDM-1, IMP-4 Totl 753 Five strins re OXA-48 producers nd colistin resistnt b Five strins re NDM producers nd colistin resistnt 96-well broth microdilution pnels with pre-loded ntibiotic-growth medium were supplied by Interntionl Helth Mngement Assocites, Inc. (Schumburg, IL, USA). Cefiderocol ws tested in iron-depleted ction-djusted Mueller Hinton broth (ID-CAMHB) [17], s recently pproved by the CLSI ( microbiology-files/), wheres comprtors were tested in ction-djusted Mueller Hinton broth (CAMHB). Qulity 2

3 Tble 2 In vitro ctivities of cefiderocol (CFDC), ceftolozne tzobctm (CT), meropenem (MEM), ceftzidime (CAZ), ceftzidime vibctm (CZA), colistin (CST), ztreonm (ATM), mikcin (AMK), ciprofloxcin (CIP), cefepime (FEP), nd tigecycline (TGC) ginst E. coli, K. pneumonie, Enterobcter sp., P. eruginos, nda. bumnnii Orgnism group/ ntimicrobil gent MIC rnge (mg/l) No. MIC 50 All species CFDC CT >64 CAZ >64 >64 CZA >64 FEP >16 >16 MEM >64 CIP >4 >4 ATM >32 >32 AMK >64 CST TGC Escherichi coli CFDC CT >64 CAZ >64 CZA >64 FEP >16 >16 MEM >64 CIP >4 >4 ATM >32 >32 AMK >64 CST TGC Klebsiell pneumonie CFDC CT >64 CAZ >64 >64 CZA >64 FEP >16 >16 MEM >64 CIP >4 >4 ATM >32 >32 AMK CST TGC Enterobcter sp. CFDC CT >64 CAZ >64 >64 CZA >64 FEP >16 >16 MEM CIP >4 >4 ATM >32 >32 AMK CST TGC

4 Tble 2 (continued) Orgnism group/ ntimicrobil gent MIC rnge (mg/l) No. MIC 50 control (QC) strins (E. coli ATCC 25922, K. pneumonie ATCC , nd P. eruginos ATCC 27853) were tested regulrly to ensure the stbility of the pnels nd vlidity of the test methods. The cceptble concentrtion rnge for QC strins is mg/l for E. coli nd P. eruginos nd not yet defined for K. pneumonie. All isoltes were tested ginst the following ntibiotics for the given concentrtion rnge: cefiderocol (S ) (CFDC, mg/l), ztreonm (ATM, mg/l), cefepime (FEP, mg/l), ceftolozne tzobctm (CT, mg/l), meropenem (MEM, mg/l), ceftzidime (CAZ, mg/l), ceftzidime vibctm (CZA, mg/l), colistin (CST, mg/l), mikcin (AMK, 4 64 mg/l), ciprofloxcin (CIP, mg/l), nd tigecycline (TGC, mg/l). The strins were grown overnight on non-selective gr medium nd two to three colonies were solubilized in 3 ml sterile 0.85% NCl. The turbidity ws djusted to 0.5 McFrlnd with McFrlnd densitometer DEN-1B from Grnt Bio (Grnt instruments Ltd., Cmbridge, UK). One milliliter of inoculum ws then diluted in 29 ml of sterile ddh 2 O nd 10 μl were dded to ech BMD pnel well. The pnels were incubted for h t 35 C. To ensure n even Pseudomons eruginos CFDC CT >64 CAZ >64 >64 CZA >64 FEP >16 >16 MEM >64 CIP >4 >4 ATM >32 AMK >64 CST TGC >4 >4 Acinetobcter bumnnii CFDC CT >64 CAZ >64 >64 CZA FEP >16 >16 MEM CIP >4 >4 ATM >32 >32 AMK >64 CST TGC MIC, minimum inhibitory concentrtion; MIC 50/90, MIC tht inhibits 50% nd 90% of the isoltes, respectively therml distribution during incubtion, the pnels were stcked no more thn four high. The MIC reding ws then done ccording to the CLSI guidelines [18]. Results nd discussion The susceptibility test results re listed in Tbles 2 7. The (MIC vlue tht inhibits 90% of the isoltes) of cefiderocol ws 2 mg/l (Tble 2), while those of comprtive drugs were >64 mg/l for CT, MEM, CAZ, CZA, nd AMK, >32 mg/l for ATM, >16 mg/l for FEP, 8 mg/l for CST, nd 2 mg/l for TGC. The MIC 50 of CFDC ws t 0.5 mg/l, while those of other drugs were >64 mg/l for CAZ, 64 mg/l for CT, >32 mg/l for ATM, >16 mg/l for FEP, 8 mg/l for MEM nd AMK, >4 mg/l for CIP, 1 mg/l for CZA, 0.5 mg/l for TGC, nd 0.5 mg/l for CST. The ddition of 4 μg/ml of vibctm restored the ctivities of ceftzidime ginst the mjority of the tested enterobcteril isoltes. The MIC 50 nd of CFDC for Enterobctericee producing KPC crbpenemses were 1 μg/ml nd 2 mg/ L, respectively (Tble 3). The only competitive comprtors were ceftzidime vibctm (MIC 50/90 )(1/4),colistin( 0.5/ 4

5 Tble 3 In vitro ctivities of cefiderocol (CFDC), ceftolozne tzobctm (CT), ceftzidime (CAZ), ceftzidime vibctm (CZA), cefepime (FEP), meropenem (MEM), ciprofloxcin (CIP), ztreonm (ATM), mikcin (AMK), colistin (CST), nd tigecycline (TGC) ginst Enterobctericee (E. coli, K. pneumonie, nd Enterobcter sp.) producing KPC-type crbpenemse Orgnism group/ntimicrobil gent MIC rnge (mg/l) No. MIC 50 Totl Enterobctericee CFDC CT >64 CAZ >64 >64 CZA FEP >16 >16 MEM >64 CIP >4 >4 ATM >32 >32 AMK CST >8 TGC Escherichi coli CFDC CT >64 CAZ >64 CZA FEP >16 >16 MEM CIP >4 >4 ATM AMK >64 CST TGC Klebsiell pneumonie CFDC CT >64 CAZ >64 >64 CZA FEP >16 >16 MEM >64 CIP >4 >4 ATM >32 >32 AMK CST >8 TGC Enterobcter sp. CFDC CT >64 CAZ >64 >64 CZA FEP >16 >16 MEM CIP >4 >4 ATM >32 >32 AMK CST TGC MIC, minimum inhibitory concentrtion; MIC 50/90, MIC tht inhibits 50% nd 90% of the isoltes, respectively 5

6 Tble 4 In vitro ctivities of cefiderocol (CFDC), ceftolozne tzobctm (CT), ceftzidime (CAZ), ceftzidime vibctm (CZA), cefepime (FEP) meropenem (MEM), ciprofloxcin (CIP), ztreonm (ATM), mikcin (AMK), colistin (CST), nd tigecycline (TGC) ginst Enterobctericee (E. coli, K. pneumonie, nd Enterobcter sp.) producing n OXA-48-type crbpenemse Orgnism group/ntimicrobil gent MIC rnge (mg/l) No. MIC 50 Totl Enterobctericee CFDC CT >64 CAZ >64 CZA FEP >16 >16 MEM CIP >4 >4 ATM >32 >32 AMK CST TGC Escherichi coli CFDC CT CAZ CZA FEP >16 MEM CIP >4 ATM >32 AMK CST TGC Klebsiell pneumonie CFDC CT >64 CAZ >64 CZA >64 FEP >16 >16 MEM CIP >4 >4 ATM >32 >32 AMK >64 CST TGC Enterobcter sp. CFDC CT >64 CAZ >64 >64 CZA FEP >16 >16 MEM CIP >4 >4 ATM >32 >32 AMK CST TGC MIC, minimum inhibitory concentrtion; MIC 50/90, MIC tht inhibits 50% nd 90% of the isoltes, respectively 6

7 Tble 5 In vitro ctivities of cefiderocol (CFDC), ceftolozne tzobctm (CT), ceftzidime (CAZ), ceftzidime vibctm (CZA), cefepime (FEP), meropenem (MEM), ciprofloxcin (CIP), ztreonm (ATM), mikcin (AMK), colistin (CST), nd tigecycline (TGC) ginst Enterobctericee (E. coli, K. pneumonie, nd Enterobcter sp.) producing NDM, VIM, or IMP crbpenemses Orgnism group/ntimicrobil gent MIC rnge (mg/l) No. MIC 50 Totl Enterobctericee CFDC CT >64 >64 CAZ >64 >64 CZA >64 >64 FEP >16 >16 MEM >64 CIP >4 >4 ATM >32 >32 AMK >64 CST TGC Escherichi coli CFDC CT >64 >64 CAZ >64 >64 CZA >64 >64 FEP >16 >16 MEM >64 CIP >4 >4 ATM >32 >32 AMK >64 CST TGC Klebsiell pneumonie CFDC CT >64 >64 CAZ >64 >64 CZA >64 >64 FEP >16 >16 MEM >64 CIP >4 >4 ATM >32 >32 AMK >64 CST TGC Enterobcter sp. CFDC CT >64 >64 CAZ >64 >64 CZA >64 >64 FEP >16 >16 MEM CIP >4 ATM >32 AMK >64 CST TGC MIC, minimum inhibitory concentrtion; MIC 50/90, MIC tht inhibits 50% nd 90% of the isoltes, respectively 7

8 Tble 6 In vitro ctivities of cefiderocol (CFDC), ceftolozne tzobctm (CT), meropenem (MEM), ceftzidime (CAZ), ceftzidime vibctm (CZA), colistin (CST), ztreonm (ATM), mikcin (AMK), ciprofloxcin (CIP), cefepime (FEP), nd tigecycline (TGC) ginst P. eruginos producing crbpenemse (either IMP, KPC, VIM, SPM, or GIM) Orgnism group/ntimicrobil gent MIC rnge (mg/l) No. MIC 50 Pseudomons eruginos CFDC CT >64 >64 CAZ >64 >64 CZA >64 >64 FEP >16 >16 MEM >64 CIP >4 >4 ATM AMK >64 CST TGC >4 MIC, minimum inhibitory concentrtion; MIC 50/90, MIC tht inhibits 50% nd 90% of the isoltes, respectively 8), nd tigecycline ( 0.5/ 1). Elevted vlues for colistin were noted for 17 out of 101 strins for K. pneumonie nd 2 out of 14 strins for Enterobcter sp. For ll other ntibiotics, the MIC 50/90 were superior or equl to the upper limit of the concentrtion rnge. OXA-48-like producing Enterobctericee were susceptible to lrger number of ntibiotics compred to the KPC producers (Tble 4). Agin, cefiderocol is one of the ntibiotics with the lowest MIC 50/90 vlues, t 0.25 nd 2 μg/ml, respectively. Direct competitors were ceftzidime vibctm (0.5/4), meropenem (1/32), mikcin ( 4/16), colistin ( 0.5/ 1), nd tigecycline ( 0.5/ 1). Agin, for Klebsiell sp., the of CZA nd MEM were ffected by outliers nd the MIC 50 vlues should be considered insted. For the enterobcteril isoltes producing NDM, VIM, or IMP crbpenemses (Tble 5), the only ntibiotics tht hd strong ctivity (MIC 50/90 ) were cefiderocol (1/4), colistin ( 0.5/ 1), nd tigecycline ( 0.25/ 1). Tble 7 In vitro ctivities of cefiderocol (CFDC), ceftolozne tzobctm (CT), meropenem (MEM), ceftzidime (CAZ), ceftzidime vibctm (CZA), colistin (CST), ztreonm (ATM), mikcin (AMK), ciprofloxcin (CIP), cefepime (FEP), nd tigecycline (TGC) ginst A. bumnnii producing n OXAtype crbpenemse (either OXA- 23, -40, -58, or -72) Colistin-resistnt strins, minly Enterobctericee, hd high susceptibility to cefiderocol ( 0.5/ 2) nd some ctivity for ceftolozne tzobctm in the cse of E. coli (0.25/>64), ceftzidime vibctm (0.5/>64), meropenem (0.12/64), mikcin ( 4/16), nd tigecycline ( 1/ 1). Except for cefiderocol nd tigecycline, the vlues were close to or bove the upper limit of the concentrtion rnge of the tested ntibiotics for the Enterobctericee being resistnt to colistin. This could be explined by dditionl resistnce trits, such s expression of genes encoding crbpenemses nd ESBLs, in prticulr for K. pneumonie nd Enterobcter sp. The level of resistnce to colistin ( = 2) nd of meropenem ( = 1) ws lower for E. coli thn tht noted for K. pneumonie nd Enterobcter sp. Crbpenemse-producing P. eruginos were susceptible only to cefiderocol (0.5/2) nd colistin ( 0.5/1) (Tble 6). The sme resistnce trend ws observed for crbpenemseproducing A. bumnnii strins [CFDC (0.12/4) nd CST Orgnism group/ntimicrobil gent MIC rnge (mg/l) No. MIC 50 Acinetobcter bumnnii CFDC CT >64 CAZ >64 >64 CZA FEP >16 >16 MEM CIP >4 >4 ATM >32 >32 AMK >64 CST TGC MIC, minimum inhibitory concentrtion; MIC 50/90, MIC tht inhibits 50% nd 90% of the isoltes, respectively 8

9 (0.5/1)], except tht they were lso susceptible to tigecycline (1/2) (Tble 7). The only unexpected result is the overll low ctivity of ceftolozne tzobctm ginst those P. eruginos isoltes. Among the 753 isoltes tested, only 24 isoltes exhibited n MIC vlue of cefiderocol 8 μg/ml, mong which 45% were NDM producers (n = 11), 30% were OXA-23-producing A. bumnnii (n = 7), nd two VEB-, one SHV-, one VIM-, nd one OXA-48-like producers mong K. pneumonie, P. eruginos, ndenterobcter sp. Noteworthy, cefiderocol ws ctive ginst 68 out of 79 NDM producers, while most of the NDM producers co-produced other β-lctm resistnce mechnisms, such s ESBLs (mostly CTX-M-15), porin defect, plsmid-medited cephlosporinses, nd other crbpenemses (dt not shown). Cefiderocol ws more ctive ( 2 4 mg/l) thn the comprtors ( >4 to >64 mg/ L) (cephlosporins, crbpenem, fluoroquinolone, nd monobctm) ginst ll the tested strins. The only comprtors with equl ctivity were colistin nd tigecycline, with the limittion tht tigecycline ws not ctive ginst P. eruginos. Finlly, it should be emphsized tht cefiderocol displys much fvorble phrmcokinetic prmeters (tissue diffusion nd use in renl impirment) thn colistin nd tigecycline [19], which will be n importnt fctor for choosing dequte therpy of infections due to multidrug infections. Complince with ethicl stndrds Funding This work ws funded by grnts from the University of Fribourg nd from Shionogi & Co., Ltd. Conflict of interest Ethicl pprovl Informed consent References None to declre. Not pplicble. Not pplicble. 1. Pitout JDD, Luplnd KB (2008) Extended-spectrum β-lctmseproducing Enterobctericee: n emerging public-helth concern. Lncet Infect Dis 8(3): Knothe H, Shh P, Krcmery V, Antl M, Mitsuhshi S (1983) Trnsferble resistnce to cefotxime, cefoxitin, cefmndole nd cefuroxime in clinicl isoltes of Klebsiell pneumonie nd Serrti mrcescens. Infection 11(6): Philippon A, Lbi R, Jcoby G (1989) Extended-spectrum β- lctmses. Antimicrob Agents Chemother 33(8): Livermore DM (2003) Bcteril resistnce: origins, epidemiology, nd impct. Clin Infect Dis 36:S11 S23 5. Gupt N, Limbgo BM, Ptel JB, Kllen AJ (2011) Crbpenemresistnt Enterobctericee: epidemiology nd prevention. Clin Infect Dis 53(1): Knj SS, Knfni ZA (2011) Current concepts in ntimicrobil therpy ginst resistnt grm-negtive orgnisms: extendedspectrum β-lctmse-producing Enterobctericee, crbpenemresistnt Enterobctericee, nd multidrug-resistnt Pseudomons eruginos.myoclinproc86(3): Poirel L, Kieffer N, Lissine N, Thnh D, Nordmnn P (2016) Plsmid-medited crbpenem nd colistin resistnce in clinicl isolte of Escherichi coli. Lncet Infect Dis 16(3): Liu YY, Wng Y, Wlsh TR, Yi LX, Zhng R, Spencer J, Doi Y, Tin G, Dong B, Hung X, Yu LF, Gu D, Ren H, Chen X, Lv L, He D, Zhou H, Ling Z, Liu JH, Shen J (2016) Emergence of plsmidmedited colistin resistnce mechnism MCR-1 in nimls nd humn beings in Chin: microbiologicl nd moleculr biologicl study. Lncet Infect Dis 16(2): Henni M, Poirel L, Kieffer N, Châtre P, Srs E, Métyer V, Dumoulin R, Nordmnn P, Mdec JY (2016) Co-occurrence of extended spectrum β lctmse nd MCR-1 encoding genes on plsmids. Lncet Infect Dis 16(3): Hsmn H, Hmmerum AM, Hnsen F, Hendriksen RS, Olesen B, Agersø Y, Znkri E, Leekitchroenphon P, Stegger M, Ks RS, Cvco LM, Hnsen DS, Arestrup FM, Skov RL (2015) Detection of mcr-1 encoding plsmid-medited colistin-resistnt Escherichi coli isoltes from humn bloodstrem infection nd imported chicken met, Denmrk Euro Surveill 20(49) 11. Kohir N, West J, Ito A, Ito-Horiym T, Nkmur R, Sto T, Rittenhouse S, Tsuji M, Ymno Y (2015) In vitro ntimicrobil ctivity of siderophore cephlosporin, S , ginst Enterobctericee clinicl isoltes, including crbpenemresistnt strins. Antimicrob Agents Chemother 60(2): Ito A, Nishikw T, Mtsumoto S, Yoshizw H, Sto T, Nkmur R, Tsuji M, Ymno Y (2016) Siderophore cephlosporin cefiderocol utilizes ferric iron trnsporter systems for ntibcteril ctivity ginst Pseudomons eruginos. Antimicrob Agents Chemother 60(12): Tillotson GS (2016) Trojn horse ntibiotics novel wy to circumvent grm-negtive bcteril resistnce? Infect Dis (Auckl) 9: Ito-Horiym T, Ishii Y, Ito A, Sto T, Nkmur R, Fukuhr N, Tsuji M, Ymno Y, Ymguchi K, Tted K (2016) Stbility of novel siderophore cephlosporin S ginst cliniclly relevnt crbpenemses. Antimicrob Agents Chemother 60(7): Ito A, Kohir N, Bouchillon SK, West J, Rittenhouse S, Sder HS, Rhomberg PR, Jones RN, Yoshizw H, Nkmur R, Tsuji M, Ymno Y (2016) In vitro ntimicrobil ctivity of S , ctechol-substituted siderophore cephlosporin, when tested ginst non-fermenting grm-negtive bcteri. J Antimicrob Chemother 71(3): Clinicl nd Lbortory Stndrds Institute (CLSI) (2015) Methods for dilution ntimicrobil susceptibility tests for bcteri tht grow erobiclly; Approved stndrds tenth edition. CLSI document M07-A10. CLSI, Wyne, PA 17. Hubnd MD, Ito A, Tsuji M, Sder HS, Fedler KA, Flmm RK (2017) Cefiderocol MIC qulity control rnges in iron-depleted ction-djusted Mueller Hinton broth using CLSI M23-A4 multi-lbortory study design. Dign Microbiol Infect Dis 88(2): Clinicl nd Lbortory Stndrds Institute (CLSI) (2015) Performnce stndrds for ntimicrobil susceptibility testing; Twenty-fifth informtionl supplement. CLSI document M100- S25. CLSI, Wyne, PA 19. Ktsube T, Wjim T, Ishibshi T, Cmilo Arjon Ferreir J, Echols R (2017) Phrmcokinetic/phrmcodynmic modeling nd simultion of cefiderocol, prenterl siderophore cephlosporin, for dose djustment bsed on renl function. Antimicrob Agents Chemother 61(1). pii: e