J Antimicrob Chemother 2017; 72: 1704 1708 doi:10.1093/jac/dkx049 Advance Access publication 22 March 2017 Activity of cefiderocol (S-649266) against carbapenem-resistant Gram-negative bacteria collected from inpatients in Greek hospitals Matthew E. Falagas 1 4 *, Tilemachos Skalidis 1,5, Konstantinos Z. Vardakas 1 3 and Nicholas J. Legakis 1,5 on behalf of the Hellenic Cefiderocol Study Group 1 Research Center of Infectious Diseases, Iaso Group Hospitals, Athens, Greece; 2 Alfa Institute of Biomedical Sciences (AIBS), Athens, Greece; 3 Department of Medicine-Infectious Diseases, Iaso General Hospital, Iaso Group, Athens, Greece; 4 Department of Medicine, Tufts University School of Medicine, Boston, MA, USA; 5 Central Laboratories, Iaso Group Hospitals, Athens, Greece *Corresponding author. Alfa Institute of Biomedical Sciences (AIBS), 9 Neapoleos Street, 151 23 Marousi, Athens, Greece. Tel:!30-694-61-10-000; Fax:!30-210-68-39-605; E-mail: m.falagas@aibs.gr Members of the Hellenic Cefiderocol Study Group are listed in the Acknowledgements. Received 21 September 2016; returned 9 January 2017; revised 20 January 2017; accepted 26 January 2017 Background: Cefiderocol (S-649266), a siderophore cephalosporin, utilizes a novel mechanism of entry into the periplasmic space of Gram-negative bacteria and is broadly stable to ESBLs and carbapenemases. Methods: A collection of carbapenem-resistant Gram-negative bacteria isolated from clinical specimens in 18 Greek hospitals was tested for susceptibility to cefiderocol, meropenem, ceftazidime, cefepime, ceftazidime/ avibactam, ceftolozane/tazobactam, aztreonam, amikacin, ciprofloxacin, colistin and tigecycline. Broth microdilution plates were used to determine MICs. Results: In total 189 non-fermentative Gram-negative bacteria (107 Acinetobacter baumannii and 82 Pseudomonas aeruginosa) and 282 Enterobacteriaceae (including 244 Klebsiella pneumoniae, 14 Enterobacter cloacae and 11 Providencia stuartii) were studied. For both A. baumannii and P. aeruginosa the MIC 90 of cefiderocol was 0.5 mg/l. For K. pneumoniae, E. cloacae and P. stuartii the MIC 90 of cefiderocol was 1, 1 and 0.5 mg/l, respectively. Tigecycline was the second most active antibiotic, followed by colistin. Conclusions: Cefiderocol exhibited greater antimicrobial activity in vitro against carbapenem-resistant Gramnegative bacteria than comparator antibiotics. Introduction Infections due to MDR and XDR Gram-negative bacteria have become a global public health problem. 1,2 Owing to the lack of new antimicrobial agents, treatment has mainly focused on older antibiotics, primarily polymyxins and secondarily fosfomycin. 3 Neither colistin nor fosfomycin has received marketing approval in the modern era. Several new antibiotics are under development for MDR and XDR Gram-negative bacteria. 4 Among them, cefiderocol (S- 649266) appears to have higher activity against MDR bacteria compared with older or upcoming antibiotics. 4 Cefiderocol is actively transported into the periplasmic space along with ferric iron, 5 binds mainly to PBP3 of Gram-negative bacteria and inhibits bacterial cell wall synthesis. 6 Cefiderocol is broadly stable to ESBLs and class A, B, C and D carbapenemases. 5,7 Published studies on the activity of cefiderocol against Gramnegative bacteria have not focused exclusively on carbapenemresistant bacteria. 5,8 We sought to investigate the in vitro antimicrobial activity of cefiderocol and that of commercially available comparator antibiotics against a collection of contemporary, clinical, carbapenem-resistant Gram-negative bacteria from inpatients from various Greek hospitals. Materials and methods Ethics The study was approved by the scientific board/ethics committee of Iaso Hospital. Isolates Non-duplicate carbapenem-resistant Gram-negative bacteria were collected from the microbiology departments of 18 Greek hospitals. Each hospital provided the available bacteria isolated over the last 7 years (2010 16). Isolates were transferred to the Research Center of Infectious VC The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com. 1704
Cefiderocol against carbapenem-resistant Gram-negative bacteria JAC Diseases of Iaso Hospital for further testing. All isolates were stored at 70 C before testing. MIC testing Frozen broth microdilution plates prepared by International Health Management Associates (IHMA; Schaumburg, IL, USA) were used to determine the MICs of cefiderocol and comparators (meropenem, ceftazidime, cefepime, ceftazidime/avibactam, ceftolozane/tazobactam, aztreonam, amikacin, ciprofloxacin, colistin and tigecycline). Cefiderocol was tested in iron-depleted CAMHB (ID-CAMHB), whereas comparators were tested in CAMHB according to current CLSI guidelines for broth microdilution testing and previously published methodology. 9,10 Plates with wells containing different concentrations of antibiotics and positive (ID-CAMHB and CAMHB) and negative control wells were stored at 70 C and thawed for 1 h before use. Plates were inoculated with a standardized suspension containing the bacterium under study and sealed. The plates were incubated for 16 20 h at 35 Cinanon-CO 2 incubator. If strong growth was confirmed in both growth control wells, reading of the MICs could proceed. Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853 and Klebsiella pneumoniae ATCC 700603 were the quality control strains used for each laboratory testing day. If the results for the ATCC quality control strains were outside the expected range recommended by the CLSI, the MIC test was repeated. The breakpoints for meropenem, ceftazidime, cefepime, aztreonam, amikacin and ciprofloxacin for all species were defined according to the CLSI (NB - the CLSI does not provide breakpoints for aztreonam for Acinetobacter baumannii). 11 Resistance to colistin for A. baumannii and P. aeruginosa was also defined according to CLSI criteria. Resistance to colistin and tigecycline for Enterobacteriaceae was defined according to EUCAST. 12 Results A total of 471 (445 meropenem resistant and 26 meropenem intermediate) isolates, collected from ICUs and wards of 18 Greek hospitals, were included [282 Enterobacteriaceae (244 K. pneumoniae,1 Klebsiella oxytoca,14enterobacter cloacae, 11 Providencia stuartii, 7 E. coli, 4 Proteus mirabilis and 1 Serratia marcescens) and 189 non-fermentative Gram-negative bacteria (107 A. baumannii and 82 P. aeruginosa)]. Table 1 shows the summary data of the MIC range, MIC 50 and MIC 90 of the antibiotics for the tested bacterial isolates and their respective resistance percentages. The MIC range, MIC 50 and MIC 90 of cefiderocol for meropenem-resistant (,0.03 4, 0.5 and 1, respectively) and meropenem-intermediate (,0.03 1, 0.12 and 0.5 mg/l, respectively) isolates were slightly different. For all 471 isolates tested, regardless of species, cefiderocol had the lowest MIC 90 values among the 11 antibiotics. The highest MIC value of cefiderocol was 4 mg/l, seen in six isolates (five K. pneumoniae and one E. cloacae). These six isolates were all resistant to meropenem, five were resistant to amikacin and ciprofloxacin (the susceptible strain was E. cloacae), one to colistin (K. pneumoniae) and none to tigecycline. The MIC range of ceftolozane/tazobactam and ceftazidime/avibactam was 32 to.64 mg/l and 1 to.64 mg/l, respectively. The cefiderocol MICs for seven E. coli isolates ranged between 0.12 and 1 mg/l and those for four P. mirabilis ranged between 0.06 and 0.5 mg/l. The single S. marcescens had a cefiderocol MIC of 0.25 mg/l and that for K. oxytoca was 0.5 mg/l. Resistance to colistin was observed in 154 isolates [including: 4 inherently resistant P. mirabilis and 11 P. stuartii isolates; 91 K. pneumoniae isolates (37.2% of all K. pneumoniae), 1 with intermediate susceptibility; 45 A. baumannii isolates (42.1% of all A. baumannii); 1 P. aeruginosa isolate (1 additional isolate showed intermediate susceptibility); and 2 E. coli isolates]. The MIC range, MIC 50 and MIC 90 of cefiderocol did not differ between colistin-resistant and colistin-susceptible A. baumannii isolates (Table 2). Slightly higher MIC 50 values were observed for colistin-resistant K. pneumoniae strains (1 versus 0.5 mg/l for all strains; Table 2); the MIC 90 was the same (1 mg/l). A few K. pneumoniae isolates (25) exhibited either resistance or intermediate resistance to tigecycline. A similar cefiderocol MIC distribution was observed for tigecycline-resistant/intermediate and tigecycline-susceptible K. pneumoniae isolates (Table 2). All P. stuartii isolates were resistant/intermediate to tigecycline. Resistance or intermediate resistance to amikacin was observed for 258 isolates (100 A. baumannii, 1 E. coli, 94 K. pneumoniae, 49 P. aeruginosa, 3P. mirabilis and 11 P. stuartii). Cefiderocol s MIC 50 for amikacin-resistant/intermediate A. baumannii isolates was identical to that for amikacin-susceptible A. baumannii; themic 90 of cefiderocol was one dilution higher among amikacin-resistant/ intermediate A. baumannii (Table 2). Amikacin-resistant/ intermediate P. aeruginosa isolates had one dilution higher MIC 50 (0.12 and 0.06 mg/l) and MIC 90 (0.5 and 0.25 mg/l) values of cefiderocol compared with that of amikacin-susceptible P. aeruginosa. Amikacin-resistant K. pneumoniae isolates had one dilution higher MIC 50 (1 and 0.5 mg/l) and MIC 90 (2 and 1 mg/l) values of cefiderocol compared with amikacin-susceptible isolates. All P. stuartii isolates were resistant to amikacin. Discussion Cefiderocol had lower MICs than any of the 10 comparator antibiotics against a collection of contemporary, clinical, carbapenemnon-susceptible Gram-negative bacterial isolates. Cefiderocol showed potent antimicrobial activity with MIC 90 values 1 mg/l for all groups of organisms. The MIC 90 of cefiderocol was lower for non-fermenting Gram-negative bacteria than for Enterobacteriaceae. Minor differences in MIC values were seen according to specific resistance phenotypes. Overall, it seems that production of carbapenemases or other broad-spectrum b-lactamases is not a significant source of resistance to cefiderocol. The catalytic efficiency of VIM-2 carbapenemases for cefiderocol was very low in a recent study, while that of KPC carbapenemases could not be determined due to minimal hydrolysis. 7 Another study showed that NDM-1-producing strains (especially E. coli) had higher MICs of cefiderocol. 5 The reason for these elevated MICs for some strains is not clear, but the deficiency of iron-transport systems in P. aeruginosa strains implicated in other siderophore b-lactams is a possible consideration. 13 However, when these same strains of P. aeruginosa were tested under similar experimental conditions, cefiderocol did not demonstrate any discrepancy between in vitro activity and in vivo efficacy as the siderophore monobactams did. 14 A few isolates with higher maximum MIC values (.32 mg/l for A. baumannii, up to 8 mg/l for P. aeruginosa and.64 mg/l for Enterobacteriaceae) have been reported in other studies. 5,8 Nevertheless, the MIC 90 s of cefiderocol for all species were low and 1705
Falagas et al. Table 1. MIC range, MIC 50 and MIC 90 of tested antibiotics for carbapenem-resistant Gram-negative bacteria and resistance rates MIC (mg/l) Resistance (%) Species/antibiotic MIC range MIC 50 MIC 90 S I R A. baumannii (n"107) cefiderocol 0.03 2 0.06 0.5 NA NA NA meropenem 8.64 64.64 0 0 100 ceftazidime 8.64.64.64 0.9 5.6 93.5 cefepime 8.16.16.16 5.6 7.5 86.9 ceftazidime/avibactam 0.25.64 32 64 NA NA NA ceftolozane/tazobactam 2.64 32.64 NA NA NA aztreonam 8.32.32.32 NA NA NA amikacin 8.64.64.64 6.5 5.6 87.9 ciprofloxacin 0.25.4.4.4 2.8 0 97.2 colistin 0.5.8 1 8 57.9 0 42.1 tigecycline 0.25 4 1 2 NA NA NA P. aeruginosa (n"82) cefiderocol 0.03 1 0.12 0.5 NA NA NA meropenem 4.64 32.64 0 14.6 85.4 ceftazidime 4.64 32.64 13.4 26.8 59.8 cefepime 1.16 16.16 25.6 43.9 30.5 ceftazidime/avibactam 1.64 16.64 NA NA NA ceftolozane/tazobactam 0.5.64.64.64 NA NA NA aztreonam 0.5.32 16.32 48.8 19.5 31.7 amikacin 4.64 64.64 40.2 8.5 51.2 ciprofloxacin 0.25.4.4.4 19.5 1.2 79.3 colistin 0.5.8 0.5 1 97.6 1.2 1.2 tigecycline 0.25.4.4.4 NA NA NA K. pneumoniae (n"244) cefiderocol 0.03 4 0.5 1 NA NA NA meropenem 2.64 32.64 0 3.3 96.7 ceftazidime 0.5.64.64.64 1.6 1.6 96.7 cefepime 1.16.16.16 0.4 1.2 98.3 ceftazidime/avibactam 0.12.64 1.64 NA NA NA ceftolozane/tazobactam 1.64.64.64 NA NA NA aztreonam 0.5.32.32.32 5.7 0.4 93.9 amikacin 4.64 16.64 61.5 14.8 23.8 ciprofloxacin 0.25.4.4.4 4.9 0.8 94.3 colistin 0.5.8 0.5.8 62.7 0 37.3 tigecycline 0.25 4 0.5 2 90.2 7.4 2.5 E. cloacae (n"14) cefiderocol 0.06 4 0.5 1 NA NA NA meropenem 2 32 4 8 0 14.3 85.7 ceftazidime.64.64.64.64 0 0 100 cefepime 16.16 16.16 0 0 100 ceftazidime/avibactam 64.64 64.64 NA NA NA ceftolozane/tazobactam 8.64.64.64 NA NA NA aztreonam 0.5 32 1 32 71.4 0 28.6 amikacin 4 8,4 8 100 0 0 ciprofloxacin 0.25.4.4.4 42.9 7.1 50 colistin 0.5 0.5 0.5 100 0 0 tigecycline 0.25 1 0.5 1 100 0 0 Continued 1706
Cefiderocol against carbapenem-resistant Gram-negative bacteria JAC Table 1 Continued MIC (mg/l) Resistance (%) Species/antibiotic MIC range MIC 50 MIC 90 S I R P. stuartii (n"11) cefiderocol 0.06 0.5 0.25 0.5 NA NA NA meropenem 2.64 32.64 0 18.2 81.8 ceftazidime.64.64.64.64 0 0 100 cefepime 16.16.16.16 0 0 100 ceftazidime/avibactam 8.64 64.64 NA NA NA ceftolozane/tazobactam 64.64.64.64 NA NA NA aztreonam 16.32.32.32 0 0 100 amikacin 64.64.64.64 0 0 100 ciprofloxacin 2.4.4.4 0 9.1 90.9 colistin.8 a.8.8 0 0 100 tigecycline 2.4 4.4 0 9.1 90.9 S, susceptible; I, intermediate resistant; R, resistant; NA, not applicable. a All isolates had MIC.8 mg/l. Table 2. Comparison of cefiderocol MIC values (mg/l) between antibiotic-resistant and antibiotic-susceptible isolates Species MIC 50 MIC 90 MIC 50 MIC 90 colistin resistant colistin susceptible A. baumannii 0.06 (n"45) 0.5 (n"45) 0.06 (n"62) 0.5 (n"62) K. pneumoniae 1(n"91) 1 (n"91) 0.5 (n"153) 1 (n"153) tigecycline resistant/intermediate (n"25) tigecycline susceptible (n"219) K. pneumoniae 0.5 1 0.5 1 amikacin resistant/intermediate amikacin susceptible A. baumannii 0.06 (n"100) 0.5 (n"100) 0.06 (n"7) 0.25 (n"7) K. pneumoniae 1(n"94) 2 (n"94) 0.5 (n"150) 1 (n"150) P. aeruginosa 0.12 (n"49) 0.5 (n"49) 0.06 (n"33) 0.25 (n"33) similar to those observed in this study. A different method for preparing iron-depleted media was utilized in these publications and therefore the studies are not directly comparable. This study used the currently approved method with ID-CAMHB. 9 In this collection of carbapenem-resistant isolates, resistance to colistin and amikacin was 32.7% and 54.8%, respectively. The second most active antibiotic was tigecycline. However, tigecycline s clinical utility is limited by several factors. First, it is not active against P. aeruginosa and its activity against A. baumannii is variable. 15 Second, tigecycline is approved for community-acquired pneumonia, intra-abdominal infections and skin infections only. Tigecycline may not be the best option for treatment of patients with bacteraemia, hospital- or ventilator-associated pneumonia and urinary tract infections (UTIs) that constitute the majority of nosocomial infections. 16 Finally, the approved dosing recommendations for infections due to susceptible bacteria may not be adequate to treat MDR/XDR bacteria. 17 Cefiderocol is currently in late-stage clinical development for complicated UTIs and carbapenem-resistant infections (NCT02321800 and NCT02714595). Based on Phase 1 pharmacokinetic exposures and Monte Carlo simulations, cefiderocol has a 90% probability of achieving ft.mic of 75% for an organism with an MIC of 4 mg/l, which was the highest MIC observed in this study. 18 Although the administration of piperacillin/tazobactam and carbapenems was associated with lower mortality, 19 cephalosporins did not consistently demonstrate better clinical outcomes when administered as prolonged infusions, but their in vivo efficacy is determined by the T.MIC principle as with other b-lactams. 20 In conclusion, cefiderocol exhibited potent antimicrobial activity in vitro against carbapenem-resistant Gram-negative bacteria, including colistin- and aminoglycoside-resistant strains. This activity did not seem to be significantly affected by specific resistance phenotypes. Thus, cefiderocol could be considered as a promising 1707
Falagas et al. candidate for the treatment of patients with infections due to carbapenem-resistant Gram-negative bacteria. Acknowledgements Members of the Hellenic Cefiderocol Study Group Dr S. Tsiplakou and Dr V. Papaioannou ( KAT General Hospital, Athens); Dr E. Trikka-Graphakos, Dr N. Charalampakis and Dr C. Sereti ( Thriassio General Hospital, Athens); Dr E. Lebessi and Dr E. Bozavoutoglou ( Aglaia Kyriakou Children s Hospital, Athens); Dr E. Vogiatzakis and Dr H. Moraiti ( Sotiria General Hospital, Athens); Dr A. Xanthaki and Dr M. Toutouza ( Ippokratio General Hospital, Athens); Dr K. Fountoulis, Dr E. Perivolioti, Dr H. Kraniotaki and Dr M. Bournia ( Evagelismos General Hospital, Athens); Dr S. Vourli ( Attikon General Hospital, Athens); Dr E. Peteinaki (General University Hospital, Larissa); Dr S. Chatzipanagiotou and Dr A. Ioannidis ( Aiginitio Hospital, Athens); Dr A. Makri, Dr M. Daskalaki and Dr E. Staikou ( Paidon Pentelis Children s Hospital, Athens); Dr K. Tzannetou and Dr H. Prifti ( Alexandra General Hospital, Athens); Dr K. Mentessidou ( Filoktitis Recovery and Rehabilitation Center, Athens); Dr A. Maltezou ( Euromedica Group, Athens); Dr E. Platsouka ( Agia Olga General Hospital, Athens); Dr N. Skarmoutsou ( Sismanogleio General Hospital, Athens); Dr I. Spiliopoulou and Dr M. Christofidou (University Hospital, Patras); Dr M. Falagas, Dr K. Vardakas, Dr N. Triarides and Dr N. Legakis ( Iaso General Hospital, Athens); Dr N. Legakis and Dr T. Skalidis ( Iaso General, Maternity and Gynecology Hospital, Athens); Dr M. Falagas and M. Kyriakidou (Alfa Institute of Biomedical Sciences, Athens). Funding This study was supported by Shionogi & Co., Ltd. Transparency declarations M. E. F. participated in advisory boards for Achaogen, AstraZeneca, Infectopharm, Tetraphase, Pfizer, Shionogi and Xellia; received lecture honoraria from Cipla, Merck, Sanofi and Novartis; and received research support from Angelini, Astellas, Rokitan and Shionogi. 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