In vitro activity of cefiderocol and comparators against isolates of Gram-negative bacterial pathogens from a range of infection sources: SIDERO‑WT‑2014−2018 studies in Spain

Journal of Global Antimicrobial Resistance 26 (2021) 292–300 Contents lists available at ScienceDirect Journal of Global Antimicrobial Resistance journal homepage: www.elsevier.com/locate/jgar In vitro activity of cefiderocol and comparators against isolates of Gram-negative bacterial pathogens from a range of infection sources: SIDERO–WT–2014 −2018 studies in Spain Emilia Cercenado a , ∗, Laura Cardenoso b , Rocio Penin c , Christopher Longshaw c , Anne Santerre Henriksen d , Alvaro Pascual e a Servicio de Microbiología y Enfermedades Infecciosas, Hospital General Universitario Gregorio Marañón/Departamento de Medicina, Facultad de Medicina, Universidad Complutense, CIBERES, Madrid, Spain b Servicio de Microbiología, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria, Hospital Universitario de La Princesa, Madrid, Spain c Infectious Diseases, Shionogi B.V., London, UK d Maxel Consulting ApS, Jyllinge, Denmark; contractor for Shionogi B.V., London, UK e Unidad Clínica de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospital Universitario Virgen Macarena/Departamento de Medicina, Universidad de Sevilla/Instituto de Biomedicina de Sevilla, Seville, Spain a r t i c l e i n f o Article history: Received 8 February 2021 Revised 10 June 2021 Accepted 17 June 2021 Available online 15 July 2021 Editor: Stefania Stefani Keywords: Cefiderocol Carbapenem resistance Gram-negative bacteria Antimicrobial resistance a b s t r a c t Objectives: The incidence of antimicrobial resistance in Europe is rising. Cefiderocol is approved in Europe for treatment of aerobic Gram-negative bacterial (GNB) infections in adults with limited treatment options. We report the in vitro activity of cefiderocol versus comparators against GNB clinical isolates from Spain. Methods: MICs were determined by broth microdilution according to International Organization for Standardization guidelines. Cefiderocol was tested using iron-depleted cation-adjusted Mueller–Hinton broth. Susceptibility rates were based on EUCAST breakpoints; if a species-specific breakpoint was unavailable, pharmacokinetic/pharmacodynamic breakpoints were used. Results: Of 2303 isolates [1502 (65.2%) Enterobacterales and 801 (34.8%) non-fermenters], 2260 (98.1%) were susceptible to cefiderocol compared with 80.8–86.9% for comparators. By infection source, susceptibility to cefiderocol ranged from 97.3% (721/741) in isolates from patients with nosocomial pneumonia to 98.9% (349/353) in bloodstream infection isolates and was greater than susceptibility to comparators (70.7–93.6% across infection sources). Overall, 368/2303 isolates (16.0%) were meropenem-resistant. A high proportion of meropenem-resistant Acinetobacter baumannii [169/175 (96.6%)] and Pseudomonas aeruginosa [48/50 (96.0%)] were cefiderocol-susceptible, similar to colistin [169/175 (96.6%) and 47/50 (94.0%), respectively] but higher than ceftazidime/avibactam [26/175 (14.9%) and 20/50 (40.0%), respectively] and ceftolozane/tazobactam [17/175 (9.7%) and 25/50 (50.0%), respectively]. All meropenemresistant Stenotrophomonas maltophilia isolates [120/120 (100%)] were cefiderocol-susceptible, including one trimethoprim/sulfamethoxazole-resistant isolate, with fewer susceptible to colistin [86/120 (71.7%)], ceftazidime/avibactam [42/120 (35.0%)] and ceftolozane/tazobactam [35/120 (29.2%)]. Conclusion: A high proportion of clinical isolates from Spain, representing a wide range of pathogens across multiple infection sources, were susceptible to cefiderocol. Cefiderocol retained activity against meropenem-resistant isolates. © 2021 The Author(s). Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ ) ∗Corresponding author. Mailing address: Servicio de Microbiología y Enfermedades Infecciosas, Hospital General Universitario Gregorio Marañón, Dr Esquerdo 46, 28007 Madrid, Spain. Tel.: + 34 91 586 8459. E-mail address: [email protected] (E. Cercenado). 1. Introduction The incidence of antimicrobial resistance in Europe is rising. A major threat to patients is the increase in carbapenem-resistant (CR) Gram-negative bacteria (GNB) as there are few therapeutic options available [ 1 , 2 ]. https://doi.org/10.1016/j.jgar.2021.06.011 2213-7165/© 2021 The Author(s). Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ ) E. Cercenado, L. Cardenoso, R. Penin et al. Journal of Global Antimicrobial Resistance 26 (2021) 292–300 As in the rest of Europe, CR-GNB infections are a substantial burden on Spanish healthcare systems [2] ; as a result, much research has been carried out into the epidemiology of CR-GNB infections. Cantón et al. estimated that ∼3.2% ( ∼12 090/372 346) of patients with nosocomial infections in Spain in 2017 had infection due to CR-GNB [mainly Pseudomonas aeruginosa ( ∼6 6 62], Acinetobacter baumannii ( ∼4620) and Klebsiella pneumoniae ( ∼809)] [3] . The CARBAR retrospective chart review of 11 040 adults admitted to hospital between April 2017 and March 2018 with confirmed GNB infection/colonisation demonstrated that 12% were infected with a CR-GNB pathogen and 63.4% (976/1539) of these were nonfermenter species [4] . Carbapenem resistance varies by pathogen, with higher levels generally observed in non-fermenter species than among Enterobacterales [3] . The prevalence of infections due to CR Enterobacterales in Spain appears to be slowly rising, with the European Centre for Disease Prevention and Control (ECDC) reporting an increase in prevalence of CR K. pneumoniae from 2.2% in 2015 to 3.8% in 2018 [1] . Correspondingly, a Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica (SEIMC) analysis concluded that the prevalence of CR K. pneumoniae was 3.9% in 2019 [5] . SEIMC also reported in 2018 that the majority of a set of 903 isolates from multidrug-resistant (MDR) GNB infections were due to CR P. aeruginosa (11.4%), extended-spectrum βlactamase (ESBL)-producing K. pneumoniae (9.4%) and CR K. pneumoniae (4.0%) [5] . A wide range of carbapenem resistance mechanisms are evident in Spanish regions. The PIRASOA surveillance programme analysed drug resistance mechanisms in 2005 MDR-GNB isolates from Andalusia from 2014–2018 [6] . A large proportion of isolates (62.0%) were carbapenemase-producers. The most common carbapenemases were found to be KPC-3 and OXA-48-like, and the prevalence of metalloβ-lactamases (MBLs) such as VIM, NDM and IMP increased dramatically from 1.5% (2/133) in 2014 to 45.5% (166/365) in 2018 [6] . In addition to the social burden of CR-GNB infections, total economic costs due to CR-GNB nosocomial infections in Spain were estimated at €472 million in 2017 [3] . There are limited treatment options available for patients with CR-GNB infections as they are often caused by MDR bacteria [7] . Although therapeutic options such as tigecycline and polymyxins are available, tigecycline outcomes are hampered by low serum concentrations of the drug and colistin is associated with considerable toxicities [8] . In addition, intrinsic resistance has been demonstrated in several species of Enterobacterales [9] . It is also important to highlight that even fewer treatment options exist for infections caused by MBL-producing GNB as current β-lactam/ βlactamase inhibitor combinations are ineffective [10] . Cefiderocol is a novel siderophore cephalosporin recently approved in Europe for the treatment of infections due to aerobic GNB organisms in adults with limited treatment options [11] and in the USA for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis, and hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia caused by GNB isolates in adults with limited or no alternative treatment options [12] . The structure of cefiderocol consists of a cephalosporin core with a catechol functional group at the 3–position side chain. The mechanism of action of cefiderocol is the same as other cephalosporins, binding primarily to penicillin-binding proteins to inhibit peptidoglycan cell wall biosynthesis. The catechol moiety differentiates cefiderocol from other cephalosporins and allows cefiderocol to be actively transported into the cell as it chelates ferric (Fe-III) iron to mimic natural siderophores [ 13 , 14 ]. The resulting increase in periplasmic concentration bypasses non-specific resistance (e.g. due to porin loss or efflux) and increases the activity of cefiderocol relative to other cephalosporins, carbapenems and β-lactam/ β-lactamase inhibitor combinations [ 12 , 15 ]. In the global SIDERO-WT surveillance studies, clinical isolates of GNB collected between 2014 and 2018 from hospitalised patients were tested against cefiderocol and comparators using recommended International Organization for Standardization (ISO) broth microdilution methodology [16] . Cefiderocol was tested using iron-depleted (iron concentration < 0.03 mg/L) cation-adjusted Mueller–Hinton broth (CAMHB) according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines [17] . Previous data published from the SIDERO-WT studies have demonstrated that cefiderocol is potent against a range of MDRGNB, including CR isolates and those producing β-lactamases from all Ambler classes, including KPC, VIM, IMP, NDM and OXA [18–20] . In this report, we focus on the clinical isolates provided for the SIDERO-WT-2014–2018 studies by hospitals in Spain. 2. Methods 2.1. Study design The full methodology for the SIDERO-WT studies and molecular characterisation of isolates by PCR has been published previously [21–23] . The presented data set represents pooled data from the SIDERO-WT studies for Spanish isolates only, collected between 2014 and 2018 with the exception of data for meropenem/vaborbactam and aztreonam/avibactam (2018). 2.2. Bacterial isolates Participating sites were instructed to collect clinical GNB isolates from patients with documented intra-abdominal, urinary tract, skin and soft tissue, respiratory tract or bloodstream infections (BSI). Isolates included Enterobacterales ( Escherichia coli, K. pneumoniae, Klebsiella spp., Enterobacter spp., Serratia spp. and Citrobacter spp.) and non-fermenters ( P. aeruginosa, A. baumannii, Burkholderia cepacia and Stenotrophomonas maltophilia ). Proteus spp., Providencia spp. and Morganella spp. were not initially included in the study but were collected from 2015 onwards. Only one isolate per patient infection episode was accepted; participating sites were requested to provide 100 isolates per site, per year. All isolates were from an unselected isolate population, collected independently of their antimicrobial susceptibility phenotype. Isolates were identified by source of infection, and subgroups were created for nosocomial pneumonia (NP), cUTI, BSI and complicated intra-abdominal infection (cIAI) (see Supplementary material for more infection source detail). 2.3. Antimicrobial susceptibility testing Isolates were tested at a central laboratory by International Health Management Associates, Inc. (IHMA, Schaumburg, IL, USA) and were identified using matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF/MS) (Bruker Daltonics, Billerica, MA, USA). Molecular characterisation was performed only in a subset of 102 meropenem-resistant isolates by PCR and sequencing. Minimum inhibitory concentrations (MICs) were determined for meropenem, ceftazidime/avibactam, ceftolozane/tazobactam, colistin and meropenem/vaborbactam by broth microdilution according to ISO guidelines [16] and for cefiderocol using EUCAST guidelines [17] . Aztreonam/avibactam was tested using ISO guidelines for aztreonam [16] with a fixed avibactam concentration of 4 mg/L. In addition, the activity of trimethoprim/sulfamethoxazole was tested only against S. maltophilia . Susceptibilities to all antibiotics, with the exception of aztreonam/avibactam, were interpreted using EUCAST breakpoints; 293 E. Cercenado, L. Cardenoso, R. Penin et al. Journal of Global Antimicrobial Resistance 26 (2021) 292–300 Table 1 In vitro activity of cefiderocol against SIDERO-WT-2014–2018 isolates from Spain by infection source Pathogen Total NP cUTI BSI/sepsis cIAI n N %S n N %S n N %S n N %S n N %S Enterobacterales 1471 1502 97.9 301 316 95.3 201 207 97.1 282 286 98.6 403 406 99.3 Escherichia coli 369 373 98.9 32 32 100 47 48 97.9 98 100 98.0 137 138 99.3 Klebsiella pneumoniae 338 356 94.9 64 75 85.3 66 71 93.0 66 67 98.5 98 98 100 Other Klebsiella spp. 202 202 100 48 48 100 25 25 100 38 38 100 51 51 100 Enterobacter cloacae 130 135 96.3 36 39 92.3 10 10 100 19 19 100 27 28 96.4 Other Enterobacter spp. 30 32 93.8 4 5 80.0 1 1 100 4 5 80.0 16 16 100 Serratia marcescens 178 179 99.4 80 80 100 12 12 100 38 38 100 13 13 100 Other Serratia spp. 9 9 100 4 4 100 ––– ––– 3 3 100 Citrobacter spp. 109 110 99.1 19 19 100 18 18 100 7 7 100 41 42 97.6 Proteus spp. 63 63 100 7 7 100 16 16 100 8 8 100 11 11 100 Morganella morganii 39 39 100 7 7 100 5 5 100 4 4 100 5 5 100 Providencia rettgeri 2 2 100 ––– 1 1 100 ––– 1 1 100 Raoultella spp. 2 2 100 ––– ––– ––– ––– Non-fermenters 789 801 98.5 420 425 98.8 75 76 98.7 67 67 100 60 62 96.8 Pseudomonas aeruginosa 372 375 99.2 191 193 99.0 33 33 100 34 34 100 34 35 97.1 Other Pseudomonas spp. 1 1 100 ––– ––– ––– ––– Acinetobacter baumannii 248 255 97.3 125 126 99.2 30 31 96.8 16 16 100 11 12 91.7 Other Acinetobacter spp. 16 16 100 6 6 100 3 3 100 ––– ––– Stenotrophomonas maltophilia 122 123 99.2 75 76 98.7 8 8 100 11 11 100 15 15 100 Burkholderia spp. 30 31 96.8 23 24 95.8 1 1 100 6 6 100 ––– Total 2260 2303 98.1 721 741 97.3 276 283 97.5 349 353 98.9 463 468 98.9 BSI, bloodstream infection; cIAI, complicated intra-abdominal infection; cUTI, complicated urinary tract infection; N , total number of isolates tested; n , total number of isolates susceptible; NP, nosocomial pneumonia; %S, percent susceptible. Table 2 Cefiderocol minimum inhibitory concentration (MIC) distribution by species for SIDERO-WT-2014–2018 isolates from Spain a Species ( n ) No. of isolates at cefiderocol MIC (mg/L) of: ≤0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32 64 Enterobacterales (1502) 454 182 245 249 192 95 54 30 1 0 0 0 Escherichia coli (373) 152 44 54 55 35 21 8 4 0 0 0 0 Klebsiella spp. (558) 182 58 66 81 70 49 34 17 1 0 0 0 Klebsiella pneumoniae (356) 101 19 31 56 57 43 31 17 1 0 0 0 Enterobacter spp. (167) 12 7 22 54 36 17 12 7 0 0 0 0 Serratia spp. (188) 30 44 61 30 20 2 0 1 0 0 0 0 Citrobacter spp. (110) 25 12 23 18 25 6 0 1 0 0 0 0 Pseudomonas aeruginosa (375) 41 57 95 101 40 28 10 3 0 0 0 0 Acinetobacter baumannii (255) 27 54 73 42 23 19 10 7 0 0 0 0 Burkholderia spp. (31) 16 6 4 2 1 1 0 0 0 0 1 0 Stenotrophomonas maltophilia (123) 38 31 26 19 5 3 0 0 0 0 0 1 a ≥20 isolates tested. where species-specific breakpoints were not available, pharmacokinetic/pharmacodynamic breakpoints were used (cefiderocol, ≤2 mg/L; colistin, ≤2 mg/L; ceftazidime/avibactam, ≤8 mg/L; and ceftolozane/tazobactam, ≤4 mg/L) [24] . Cefiderocol was tested using iron-depleted (iron concentration < 0.03 mg/L) CAMHB [17] , necessary to promote the natural production of siderophores by bacterial cells. All other antimicrobial agents were tested using standard CAMHB. Quality control testing was performed on each day of testing. 2.4. Statistical analysis Post-hoc statistical analysis was carried out. Odds ratios with 95% confidence intervals were calculated based on the assumption that the odds ratio is normally distributed. Significance was determined by the null value (1) lying outside of the confidence interval. 3. Results 3.1. Epidemiology and cefiderocol data 3.1.1. Epidemiology Twelve sites across Spain participated in the study (see Supplementary material for details of participating centres). In total, 2303 GNB clinical isolates were collected between 2014 and 2018; 1502 (65.2%) were Enterobacterales and 801 (34.8%) were non-fermenters. The most common Enterobacterales were E. coli [373/1502 (24.8%)] and K. pneumoniae [356/1502 (23.7%)]. The most common non-fermenters were P. aeruginosa [375/801 (46.8%)], A. baumannii [255/801 (31.8%)] and S. maltophilia [123/801 (15.4%)]. 3.1.2. Cefiderocol results by infection source Cefiderocol demonstrated activity against a wide range of pathogens regardless of the source of infection ( Table 1 ). Susceptibility to cefiderocol across infection sources ranged from 97.3% in NP to 98.9% in BSI and cIAI. 3.1.3. Cefiderocol results by pathogen A high proportion of isolates were susceptible to cefiderocol, ranging from 93.8% of Enterobacter spp . [with the exception of Enterobacter cloacae (96.3%)] to 100% of Serratia spp., Proteus spp., Providencia spp., Morganella spp. and Acinetobacter spp. (with the exception of A. baumannii ) ( Table 1 ). Data for cefiderocol MIC distribution by species are presented in Table 2 . In total, 43/2303 (1.9%) isolates were cefiderocol-resistant (MIC > 2 mg/L). Of these cefiderocol-resistant isolates, 31 were Enterobacterales (30 with MIC of 4 mg/L and 1 with MIC of 8 mg/L) including 18 K. pneumoniae . Moreover, 27 of the cefiderocolresistant Enterobacterales were meropenem-susceptible, 16 were 294 E. Cercenado, L. Cardenoso, R. Penin et al. Journal of Global Antimicrobial Resistance 26 (2021) 292–300 Table 3 In vitro activity of cefiderocol and comparators against SIDERO-WT-2014–2018 isolates from Spain Species ( n ) a Antimicrobial agent MIC (mg/L) MIC interpretation (%S) a Range MIC 50 MIC 90 Enterobacterales (1502) Cefiderocol < 0.002–8 0.12 1 97.9 Meropenem < 0.06 to > 64 < 0.06 0.12 98.9 Ceftolozane/tazobactam < 0.06 to > 64 0.25 2 90.6 Ceftazidime/avibactam < 0.03 to > 64 0.12 0.5 98.7 Colistin < 0.25 to > 8 0.5 > 8 78.3 Meropenem/vaborbactam ( n = 311) < 0.06–8 < 0.06 < 0.06 99.7 Aztreonam/avibactam ( n = 311) < 0.12–2 < 0.12 0.25 NA Escherichia coli (373) Cefiderocol < 0.002–4 0.06 0.5 98.9 Meropenem < 0.06 to > 64 < 0.06 < 0.06 99.7 Ceftolozane/tazobactam < 0.06 to > 64 0.25 0.5 98.9 Ceftazidime/avibactam < 0.03–32 0.12 0.25 99.5 Colistin < 0.25–2 0.5 1 100 Meropenem/vaborbactam ( n = 76) < 0.06–0.12 < 0.06 < 0.06 100 Aztreonam/avibactam ( n = 76) < 0.12–< 0.12 < 0.12 < 0.12 NA Klebsiella spp. (558) Cefiderocol < 0.002–8 0.12 1 96.8 Meropenem < 0.06 to > 64 < 0.06 0.5 98.0 Ceftolozane/tazobactam 0.12 to > 64 0.25 8 85.5 Ceftazidime/avibactam < 0.06 to > 64 0.25 1 98.6 Colistin < 0.25 to > 8 0.5 1 96.4 Meropenem/vaborbactam ( n = 114) < 0.06–8 < 0.06 < 0.06 100 Aztreonam/avibactam ( n = 114) < 0.12–1 < 0.12 0.25 NA Klebsiella pneumoniae (356) Cefiderocol < 0.002–8 0.25 2 94.9 Meropenem < 0.06 to > 64 < 0.06 2 97.2 Ceftolozane/tazobactam 0.12 to > 64 0.25 32 80.9 Ceftazidime/avibactam < 0.06 to > 64 0.25 1 97.8 Colistin < 0.25 to > 8 0.5 2 94.7 Meropenem/vaborbactam ( n = 76) < 0.06–0.12 < 0.06 < 0.06 100 Aztreonam/avibactam ( n = 76 < 0.12–1 < 0.12 0.25 NA Serratia spp. b (188) Cefiderocol 0.008–4 0.12 0.5 99.5 Meropenem < 0.06–64 < 0.06 0.12 99.5 Ceftolozane/tazobactam 0.12 to > 64 0.5 1 96.8 Ceftazidime/avibactam < 0.03 to > 64 0.25 1 97.3 Colistin < 0.25 to > 8 > 8 > 8 6.4 Meropenem/vaborbactam ( n = 49) < 0.06–0.25 < 0.06 0.12 100 Aztreonam/avibactam ( n = 49) < 0.12–1 < 0.12 0.25 NA Citrobacter spp. (110) Cefiderocol < 0.002–4 0.12 0.5 99.1 Meropenem < 0.06–1 < 0.06 < 0.06 100 Ceftolozane/tazobactam 0.12–8 0.25 0.5 93.6 Ceftazidime/avibactam < 0.06–1 0.12 0.25 100 Colistin < 0.25–2 0.5 1 100 Meropenem/vaborbactam ( n = 24) < 0.06–< 0.06 < 0.06 < 0.06 100 Aztreonam/avibactam ( n = 24) < 0.12–0.5 < 0.12 < 0.12 NA Enterobacter spp. (167) Cefiderocol < 0.002–4 0.25 2 95.8 Meropenem < 0.06–64 < 0.06 1 97.6 Ceftolozane/tazobactam 0.12 to > 64 0.25 32 76.0 Ceftazidime/avibactam < 0.06 to > 64 0.25 1 97.6 Colistin < 0.25 to > 8 0.5 > 8 84.4 Meropenem/vaborbactam ( n = 33) < 0.06–2 < 0.06 0.12 97.0 Aztreonam/avibactam ( n = 33) < 0.12–2 < 0.12 1 NA Proteus spp. b (63) Cefiderocol 0.004–0.5 0.015 0.12 100 Meropenem < 0.06–0.5 < 0.06 0.12 100 Ceftolozane/tazobactam 0.25–1 0.25 1 100 Ceftazidime/avibactam < 0.06–0.25 < 0.06 0.12 100 Colistin > 8 to > 8 > 8 > 8 0 Meropenem/vaborbactam ( n = 8) < 0.06–0.12 NA NA 100 Aztreonam/avibactam ( n = 8) < 0.12 NA NA NA Morganella morganii b (39) Cefiderocol 0.015–0.5 0.12 0.5 100 Meropenem < 0.06–0.12 0.12 0.12 100 Ceftolozane/tazobactam 0.12–32 0.25 0.5 92.3 Ceftazidime/avibactam < 0.06–0.5 < 0.06 0.12 100 Colistin > 8 to > 8 > 8 > 8 0 Meropenem/vaborbactam ( n = 5) < 0.06–< 0.06 NA NA 100 Aztreonam/avibactam ( n = 5) < 0.12–< 0.12 NA NA NA Nonfermenters (801) Cefiderocol < 0.002–64 0.12 1 98.5 Meropenem < 0.06 to > 64 8 > 64 56.2 Ceftolozane/tazobactam < 0.06 to > 64 1 64 62.4 Ceftazidime/avibactam < 0.06 to > 64 4 64 64.8 Colistin < 0.25 to > 8 1 4 89.5 Meropenem/vaborbactam ( n = 165) < 0.06 to > 64 2 64 60.6 Aztreonam/avibactam ( n = 165) 0.25 to > 8 8 > 8 NA ( continued on next page ) 295 E. Cercenado, L. Cardenoso, R. Penin et al. Journal of Global Antimicrobial Resistance 26 (2021) 292–300 Table 3 ( continued ) Species ( n ) a Antimicrobial agent MIC (mg/L) MIC interpretation (%S) a Range MIC 50 MIC 90 Pseudomonas aeruginosa (375) Cefiderocol < 0.002–4 0.12 1 99.2 Meropenem < 0.06 to > 64 0.5 16 86.7 Ceftolozane/tazobactam < 0.06 to > 64 0.5 4 92.3 Ceftazidime/avibactam < 0.06 to > 64 2 8 91.5 Colistin < 0.25 to > 8 1 2 98.4 Meropenem/vaborbactam ( n = 73) < 0.06–64 0.5 16 89.0 Aztreonam/avibactam ( n = 73) 0.25 to > 8 8 > 8 NA Acinetobacter spp. (271) Cefiderocol 0.004–4 0.12 1 97.4 Meropenem < 0.06 to > 64 64 > 64 35.1 Ceftolozane/tazobactam < 0.06 to > 64 8 64 37.6 Ceftazidime/avibactam 1 to > 64 16 64 38.7 Colistin < 0.25 to > 8 0.5 2 95.6 Meropenem/vaborbactam ( n = 54) 0.12 to > 64 64 64 42.6 Aztreonam/avibactam ( n = 54) 1 to > 8 > 8 > 8 NA Acinetobacter baumannii (255) Cefiderocol 0.004–4 0.12 1 97.3 Meropenem 0.12 to > 64 64 > 64 31.4 Ceftolozane/tazobactam < 0.06 to > 64 8 64 33.7 Ceftazidime/avibactam 1 to > 64 32 64 35.7 Colistin < 0.25 to > 8 0.5 2 95.3 Meropenem/vaborbactam ( n = 49) 0.12 to > 64 64 64 36.7 Aztreonam/avibactam ( n = 49) 8 to > 8 > 8 > 8 NA Burkholderia spp. b (31) Cefiderocol < 0.002–32 0.03 0.25 96.8 Meropenem 2–32 8 16 83.9 Ceftolozane/tazobactam 0.5 to > 64 8 > 64 45.2 Ceftazidime/avibactam 0.25–32 4 16 83.9 Colistin 8 to > 8 > 8 > 8 0 Meropenem/vaborbactam ( n = 12) 1–16 NA NA 91.7 Aztreonam/avibactam ( n = 12) 2–8 NA NA NA Stenotrophomonas maltophilia c (123) Cefiderocol 0.008–64 0.06 0.25 99.2 Meropenem 1 to > 64 > 64 > 64 2.4 Ceftolozane/tazobactam 0.12 to > 64 16 > 64 30.1 Ceftazidime/avibactam 0.5 to > 64 16 > 64 35.8 Colistin < 0.25 to > 8 2 8 71.5 Meropenem/vaborbactam ( n = 25) 32 to > 32 > 32 > 32 0 Aztreonam/avibactam ( n = 25) 1–8 4 8 NA MIC, minimum inhibitory concentration; MIC 50/90 , MIC of 50% and 90% of the tested isolates, respectively; NA, not applicable ( < 20 isolates or no breakpoint available); %S, percent susceptible. a Where n ≥20 isolates. b Intrinsically resistant to colistin. c Intrinsically resistant to meropenem. colistin-susceptible, 28 were ceftazidime/avibactam-susceptible and 8 were ceftolozane/tazobactam-susceptible. In total, 12/801 (1.5%) non-fermenters were resistant to cefiderocol (10 isolates with MIC of 4 mg/L and one each with MIC of 32 mg/L and 64 mg/L), including 7 A. baumannii and 3 P. aeruginosa. Of these cefiderocol-resistant non-fermenters, 1 was meropenem-susceptible, 10 were colistin-susceptible, 1 was ceftazidime/avibactam-susceptible, 1 was ceftolozane/tazobactamsusceptible and 1 was aztreonam/avibactam-susceptible. The most common infection source of cefiderocol-resistant isolates was NP ( n = 20). 3.1.4. Cefiderocol versus comparators The isolate collection contained a wide range of pathogens, including some species that display intrinsic resistance to specific comparators; Proteus spp., Providencia spp., Morganella spp., Serratia spp. and Burkholderia spp. are intrinsically resistant to colistin [9] , while S. maltophilia is intrinsically resistant to meropenem [25] . In vitro activity data for cefiderocol and comparators are shown in Table 3 . Susceptibility to all antimicrobials was generally similar in species that are not intrinsically resistant to certain agents. However, susceptibility to cefiderocol was greater than ceftolozane/tazobactam in Klebsiella spp., Citrobacter spp. and Enterobacter spp. In addition, susceptibility to cefiderocol was greater than β-lactam/ β-lactamase inhibitor combinations in non-fermenters, especially Acinetobacter spp. and S. maltophilia . A significantly ( P < 0.01) higher proportion of isolates was susceptible to cefiderocol [2260/2303 (98.1%)] compared with comparators overall and across all infection sources ( Table 4 ). The proportion of Enterobacterales susceptible to cefiderocol ranged from 95.3% (301/316) in NP to 99.3% (403/406) in cIAI, and was significantly ( P < 0.01) greater than the proportion of Enterobacterales susceptible to ceftolozane/tazobactam overall (97.9% vs. 90.5%) and for all infection sources. Susceptibility to cefiderocol in Enterobacterales was similar to meropenem and ceftazidime/avibactam overall and across all infection sources. Due to intrinsic resistance to Proteus spp., Providencia spp., Morganella spp. and Serratia spp., colistin showed variation across infection sources for Enterobacterales. The proportion of all Enterobacterales isolates susceptible to cefiderocol was significantly ( P < 0.01) higher than to colistin [1176/1502 (78.3%)] overall. However, excluding Proteus spp., Providencia spp., Morganella spp. and Serratia spp., susceptibility to cefiderocol in Enterobacterales [1180/1210 (97.5%)] was similar to colistin [1164/1210 (96.2%)]. A significantly ( P < 0.01) greater proportion of non-fermenters was susceptible to cefiderocol than all other antimicrobials tested. Susceptibility to cefiderocol [789/801 (98.5%)] was significantly ( P < 0.01) greater than to ceftolozane/tazobactam [500/801 (62.4%)] 296 E. Cercenado, L. Cardenoso, R. Penin et al. Journal of Global Antimicrobial Resistance 26 (2021) 292–300 Table 4 In vitro susceptibility of cefiderocol and comparators against Enterobacterales, non-fermenters and overall, by infection source, for SIDERO-WT-2014–2018 isolates from Spain Infection source Pathogen group ( n ) a Antimicrobial agent (% susceptible) CFDC MEM C/T CZA CST MVB b ( n ) Overall Enterobacterales (1502) 97.9 98.9 90.5 ∗∗ 98.7 78.3 ∗∗ 99.7 (311) Non-fermenters (801) 98.5 56.2 ∗∗ 62.4 ∗∗ 64.8 ∗∗ 89.5 ∗∗ 60.6 (165) All (2303) 98.1 84.0 ∗∗ 80.8 ∗∗ 86.9 ∗∗ 82.2 ∗∗ 86.1 (476) NP Enterobacterales (316) 95.3 98.7 86.1 ∗∗ 97.8 67.1 ∗∗ 98.7 (77) Non-fermenters (425) 98.8 53.6 ∗∗ 59.3 ∗∗ 62.6 ∗∗ 86.4 ∗∗ 57.1 (1684) All (741) 97.3 72.9 ∗∗ 70.7 ∗∗ 77.6 ∗∗ 78.1 ∗∗ 77.0 (161) cUTI Enterobacterales (207) 97.1 99.0 90.9 ∗99.0 81.6 ∗∗ 100 (42) Non-fermenters (76) 98.7 51.3 ∗∗ 65.8 ∗∗ 68.4 ∗∗ 93.4 43.8 (16) All (283) 97.5 86.2 ∗∗ 84.5 ∗∗ 90.8 ∗∗ 84.8 ∗∗ 84.5 (58) BSI Enterobacterales (286) 98.6 99.0 90.9 ∗∗ 99.0 80.8 ∗∗ 100 (77) Non-fermenters (67) 100 58.2 † 67.2 † 67.2 † 83.6 † 50.0 (18) All (353) 98.9 91.2 ∗∗ 86.4 ∗∗ 92.9 ∗∗ 81.3 ∗∗ 90.5 (95) cIAI Enterobacterales (406) 99.3 99.0 91.1 ∗∗ 98.8 88.4 ∗∗ 98.0 (51) Non-fermenters (62) 96.8 58.1 ∗∗ 58.1 ∗∗ 58.1 ∗∗ 93.5 100 (1) All (468) 98.9 93.6 ∗∗ 86.8 ∗∗ 93.4 ∗∗ 89.1 ∗∗ 98.1 (52) BSI, bloodstream infection; CFDC, cefiderocol; cIAI, complicated intra-abdominal infection; CST, colistin; C/T, ceftolozane/tazobactam; cUTI, complicated urinary tract infection; CZA, ceftazidime/avibactam; MEM, meropenem; MVB, meropenem/vaborbactam; NP, nosocomial pneumonia. a Enterobacterales includes isolates with intrinsic colistin resistance ( n = 323); non-fermenters includes isolates with intrinsic meropenem resistance ( n = 123) and those with intrinsic colistin resistance ( n = 31). b Isolates collected in 2017/2018 only ( n = 476), no statistical analysis available. ∗P < 0.05 versus cefiderocol; ∗∗ P < 0.01 versus cefiderocol; † insufficient data to provide measure of significance. Table 5 In vitro activity of cefiderocol and comparators against meropenem-resistant (MIC > 8 mg/L) SIDERO-WT-2014–2018 isolates from Spain Species ( n ) a Antimicrobial agent MIC (mg/L) MIC interpretation (%S) Range MIC 50 MIC 90 Acinetobacter baumannii (175) Cefiderocol 0.015–4 0.25 1 96.6 Ceftazidime/avibactam 4 to > 64 32 > 64 14.9 Ceftolozane/tazobactam 2 to > 64 16 > 64 9.7 Colistin < 0.25 to > 8 0.5 2 96.6 Pseudomonas aeruginosa (50) Cefiderocol 0.06–4 0.25 2 96.0 Ceftazidime/avibactam 4 to > 64 16 > 64 40.0 Ceftolozane/tazobactam 0.5 to > 64 4 > 64 50.0 Colistin < 0.25–4 1 1 94.0 Stenotrophomonas maltophilia (123) b Cefiderocol 0.015–1 0.06 0.25 100 Ceftazidime/avibactam 1 to > 64 16 > 64 35.0 Ceftolozane/tazobactam 0.25 to > 64 16 > 64 29.2 Colistin < 0.25 to > 8 2 8 71.7 MIC, minimum inhibitory concentration; MIC 50/90 , MIC of 50% and 90% of the tested isolates, respectively; %S, percent susceptible. a Where n ≥20 isolates. b Intrinsically resistant to meropenem. and ceftazidime/avibactam [519/801 (64.8%)] in non-fermenters overall and across NP, cUTI and cIAI infection sources. Susceptibility to cefiderocol was also substantially numerically higher than both β-lactam/ β-lactamase combinations in BSI non-fermenters, but significance could not be determined due to the low number of available isolates. The proportion of non-fermenters susceptible to cefiderocol [789/801 (98.5%)] was significantly ( P < 0.01) greater than to colistin against non-fermenters overall [717/801 (89.5%)] and in NP. Excluding intrinsically colistin-resistant Burkholderia spp. from the non-fermenters, cefiderocol retained higher activity than colistin overall [cefiderocol, 759/770 (98.6%); colistin, 717/770 (93.1%)] and in NP [cefiderocol, 397/401 (99.0%); colistin, 367/401 (91.5%)]. Aztreonam/avibactam and meropenem/vaborbactam were tested only against isolates from 2018 ( n = 476) ( Table 3 ). The aztreonam/avibactam MIC 90 was 0.25 mg/L against Enterobacterales ( n = 311) and > 8 mg/L against non-fermenters ( n = 165). The meropenem/vaborbactam MIC 90 was < 0.06 mg/L against Enterobacterales and 64 mg/L against non-fermenters. Susceptibility to meropenem/vaborbactam was substantially higher in Enterobacterales (99.7%) compared with non-fermenters (60.6%). 3.2. Meropenem-resistant isolates Of the 2303 isolates tested, 368 (16.0%) were meropenemresistant (MIC > 8 mg/L) ( Table 5 ). A higher proportion of NP isolates was meropenem-resistant [201/741 (27.1%)] compared with other infection sources [cUTI, 39/283 (13.8%); BSI, 31/353 (8.8%); cIAI, 30/468 (6.4%)]. Only 1.1% (17/1502) of Enterobacterales were meropenem-resistant. By contrast, 43.8% (351/801) of non-fermenters were meropenem-resistant [50/375 (13.3%) of P. aeruginosa and 175/255 (68.6%) of A. baumannii ]. Excluding S. maltophilia isolates with expected intrinsic resistance ( n = 123), 11.4% (248/2180) of isolates were meropenem-resistant. 297 E. Cercenado, L. Cardenoso, R. Penin et al. Journal of Global Antimicrobial Resistance 26 (2021) 292–300 A high proportion of meropenem-resistant A. baumannii, P. aeruginosa and S. maltophilia isolates remained susceptible to cefiderocol ( Table 5 ). Susceptibility to cefiderocol was similar to that of colistin against A. baumannii (cefiderocol, 96.6%; colistin, 96.6%) and P. aeruginosa (cefiderocol, 96.0%; colistin, 94.0%), while susceptibility to cefiderocol was numerically higher versus S. maltophilia (cefiderocol, 100%; colistin, 71.7%). Ceftazidime/avibactam and ceftolozane/tazobactam did not demonstrate high levels of activity against meropenem-resistant non-fermenters and it is notable that 50% of meropenem-resistant P. aeruginosa were resistant to ceftolozane/tazobactam. Only S. maltophilia isolates collected in 2018 ( n = 25) were tested against trimethoprim/sulfamethoxazole. One S. maltophilia isolate was resistant to trimethoprim/sulfamethoxazole (MIC = 4 mg/L) and all other comparator antimicrobials with the exception of cefiderocol (MIC = 0.06 mg/L); no aztreonam/avibactam breakpoint was available, but the MIC was 1 mg/L. The remaining 24 S. maltophilia isolates had trimethoprim/sulfamethoxazole MICs in the range between ≤0.012 mg/L and 1 mg/L. Molecular characterisation was carried out for 102 meropenemresistant isolates. The majority ( n = 76) were A. baumannii , all of which were susceptible to cefiderocol; 37 OXA-23 and 37 OXA- 24 carriers were identified, and 2 had no transferable β-lactamase genes. Of 20 P. aeruginosa isolates, 6 had VIM identified (3 VIM- 20, 2 VIM-2 and 1 VIM-4), all of which were susceptible to cefiderocol, and 14 isolates had no transferable β–lactamases detected, with 1 isolate being resistant to cefiderocol. Identified genes in the four K. pneumoniae isolates were two OXA-48-like and two VIM-1; one VIM-1-producer was cefiderocol-resistant (MIC = 4 mg/L). The remaining two isolates were both susceptible to cefiderocol—one VIM–1 Enterobacter asburiae and one Serratia marcescens with no transferable β-lactamases detected. 4. Discussion In this subset of Spanish isolates from the SIDERO-WT-2014– 2018 study, cefiderocol demonstrated in vitro activity against GNB isolates from different infection sources. A significantly ( P < 0.01) higher proportion of isolates was susceptible to cefiderocol compared with all comparators, and cefiderocol activity was similar across infection sources ( Table 4 ). Susceptibility to cefiderocol in Enterobacterales was significantly ( P < 0.01) greater than to ceftolozane/tazobactam and colistin, but similar to meropenem and ceftazidime/avibactam, while susceptibility to cefiderocol in non-fermenters was significantly ( P < 0.01) greater than comparators. Of particular note is the fact that cefiderocol activity was significantly ( P < 0.01) greater than all comparators against isolates from patients with NP. Few isolates were cefiderocolresistant [43/2303 (1.9%)]. It is worth noting that 30/31 (96.8%) of cefiderocol-resistant Enterobacterales had an MIC of 4 mg/L and would be interpreted as susceptible using US Food and Drug Administration (FDA) or Clinical and Laboratory Standards Institute (CLSI) breakpoints [ 26 , 27 ]. Cefiderocol retained activity against meropenem-resistant isolates. The study is limited by the fact that there are low numbers of isolates for some species by infection source, in particular nonfermenters in cUTI, BSI and cIAI sites. Furthermore, species such as Proteus spp., Providencia spp., Morganella spp. and Burkholderia spp. were not collected for the full duration of the study, and newer βlactam/ β-lactamase combinations (meropenem/vaborbactam and aztreonam/avibactam) were only included as comparators in 2018, so data are limited. Data on mechanisms of resistance are also incomplete, as molecular characterisation was only carried out for a subset of isolates. Participating sites were located primarily in cities, with one site in Mallorca; a third of the sites were located in Madrid, and no sites were located in the North-West region of Spain. The general epidemiology for isolates from Spain is very similar to the SIDERO-WT overall European epidemiology, with the proportion of Enterobacterales in Spain [1502/2303 (65.2%)] similar to that for all of Europe [13 926/20 909 (66.6%)]. This is also comparable with data from the PIRASOA programme which found that 750/1243 isolates (60.3%) tested were Enterobacterales [6] . In this analysis, Enterobacterales are less relevant than nonfermenters for clinicians in Spain as a smaller proportion of Enterobacterales were meropenem-resistant compared with non-fermenters. In the SIDERO-WT-2014–2018 study, the overall prevalence of meropenem-resistant Enterobacterales in Spain [17/1502 (1.1%)] was similar to the European average [384/13 926 (2.8%)]. Meropenem resistance was much more prevalent in nonfermenters from Spain [351/801 (43.8%)] than Enterobacterales but was also similar to the European average [2847/6983 (40.8%)]. Of the EU5 (France, Germany, Italy, Spain and UK), only Italy [516/927 (55.7%)] had a higher prevalence of meropenem-resistant nonfermenter isolates than Spain. The proportions of meropenem-resistant isolates for key species in SIDERO-WT are relatively consistent with previously published reports on the prevalence of carbapenem resistance for K. pneumoniae [SIDERO-WT, 3.9% (10/256); ECDC, 3.8%; Cantón, 2.7%], P. aeruginosa [SIDERO-WT, 13.3% (50/375); ECDC, 18.6%; Cantón, 18.4%] and A. baumannii [SIDERO-WT, 68.6% (175/255); ECDC, 53.4% Acinetobacter spp.; Cantón, 68.2% Acinetobacter spp.) [ 1 , 3 ]. Ceftolozane/tazobactam is commonly used to treat infections caused by P. aeruginosa , although activity against other nonfermenter species is generally limited [ 28 , 29 ]. In this study, susceptibility to ceftolozane/tazobactam (92.3%) for P. aeruginosa was higher than to ceftazidime/avibactam (91.5%) and meropenem (86.7%), but lower than that of colistin (98.4%) and cefiderocol (99.2%). Overall susceptibility to ceftolozane/tazobactam in non-fermenters was 62.4% due to the low susceptibility of other non-fermenter species ( Acinetobacter spp., 37.6%; Burkholderia spp., 45.2%; S. maltophilia , 30.1%). Susceptibility to ceftazidime/avibactam (64.8%) was similar to ceftolozane/tazobactam (62.4%) overall versus non-fermenters. The SUPERIOR multicentre study from intensive care units in Spain reported that 95.7% (44/46; MIC 90 = 4 mg/L) of P. aeruginosa isolates from cUTI were susceptible to ceftolozane/tazobactam [30] . Similarly, the SIDERO-WT studies found that 93.9% (31/33; MIC 90 = 1 mg/L) of P. aeruginosa isolates from cUTI were susceptible to ceftolozane/tazobactam. The SUPERIOR study also reported that 85.3% (29/34; MIC 90 = 64 mg/L) of P. aeruginosa isolates from cIAI were susceptible to ceftolozane/tazobactam [30] , while the proportion of cIAI P. aeruginosa isolates susceptible to ceftolozane/tazobactam [33/35 (94.3%); MIC 90 = 1 mg/L] in SIDERO-WT was higher. The SUPERIOR study reported no activity of ceftolozane/tazobactam against carbapenemase-producing isolates [30] . In contrast to this, 48/50 (96.0%) of meropenemresistant P. aeruginosa isolates were susceptible to cefiderocol in this study. As expected, the MIC 90 for both aztreonam/avibactam and meropenem/vaborbactam was lower in Enterobacterales (0.25 mg/L and < 0.06 mg/L, respectively) than in non-fermenters ( > 8 mg/L and 64 mg/L, respectively). Vaborbactam is active against GNB pathogens producing class A carbapenemases [31] but is not able to inhibit class B or D carbapenemases frequently detected in non-fermenters [31] . The prevalence of MBL-producing GNB is increasing, particularly in the south of Spain. For example, between 2014 and 2018 the prevalence of MBLs increased substantially from 1.5% (2/133) to 45.5% (166/365) in carbapenemase-producing GNB isolates collected from hospitals participating in the PIRASOA surveillance programme in Andalusia [6] . Longshaw et al. report from an in 298 E. Cercenado, L. Cardenoso, R. Penin et al. Journal of Global Antimicrobial Resistance 26 (2021) 292–300 vitro isolate study that cefiderocol demonstrated favourable activity when tested against a set of CR and MDR isolates harbouring a range of MBLs [20] . Of the antimicrobials tested, only cefiderocol and colistin had susceptibility rates of > 50% versus VIM-producing Enterobacterales (cefiderocol, 79.0%; colistin, 93.5%), NDM-producing Enterobacterales (cefiderocol, 51.4%; colistin, 78.4%) and VIM- and GES-producing P. aeruginosa (cefiderocol, 100%; colistin, 100%) [20] . Similarly, among the meropenemresistant Spanish isolates in the SIDERO-WT studies with available mechanisms of resistance data, 5/6 isolates with VIM genes detected that were tested were susceptible to cefiderocol and 5/6 were susceptible to colistin; none were susceptible to ceftazidime/avibactam or ceftolozane/tazobactam. This study confirms previous reports that cefiderocol is active against a broad range of GNB from all types of infections [21– 23] . However, there were low numbers of isolates highly resistant to other antimicrobials, meaning that many of the isolates in this study have other therapeutic alternatives. Full molecular characterisation was carried out for only a subset of meropenemresistant isolates. The high number of isolates susceptible to antimicrobials tested may be due to low numbers of MBL-producing or ESBL-producing isolates. The PIRASOA programme reported a high prevalence (45.5%) of MBLs in 2018 [6] . Notably, MBL production was substantially lower (1.5%) in 2014 at the start of the PIRASOA programme [6] . Although the SIDERO-WT isolates were collected at the same time as the PIRASOA isolates, the SIDEROWT isolates were unselected and were taken from multiple sites across Spain, meaning that it is not appropriate to compare prevalence data. Cefiderocol is a promising alternative when few other treatment options for CR-GNB infections are available. Of particular importance is the activity of cefiderocol against MBL-producing GNB; the number of infections caused by MBL-producing GNB is increasing, but there are very few effective treatment options for such infections. Cefiderocol is active against MBL-producers and therefore could be a promising therapeutic option where MBL production is suspected [20] . A particular issue in Spain at present is the rapid dissemination of high-risk clones of GNB. Spread of KPC-producing K. pneumoniae clones ST11, ST101 and ST512 has occurred across multiple regions; ST101 is of particular concern owing to its hypervirulence and extensive resistance profile [32] . High-risk clones of P. aeruginosa (ST235, ST111 and ST175) in Spain have also been characterised [33] . It is concerning that P. aeruginosa ST235 is resistant to aminoglycosides, β-lactams and carbapenems and has been associated with transferable resistance [33] . Although strain information on the isolates in the SIDERO-WT studies are not available, cefiderocol is active against the vast majority of K. pneumoniae and P. aeruginosa isolates tested, including 96.0% of meropenemresistant P. aeruginosa isolates, indicating the potential utility of cefiderocol in the clinical setting in Spain, regardless of strain identity. An important aspect of controlling the spread of antimicrobial resistance is antibiotic stewardship. Carbapenems are widely considered to be a last-line treatment for patients with MDR-GNB infections. However, resistance to carbapenems is increasing and diversification of antibiotics is needed. While other options for CRGNB infections exist, such as polymyxins, there are concerns about neurotoxicity and nephrotoxicity associated with these treatments [34] . Published clinical trial data on cefiderocol demonstrate that it is well tolerated and has a safety profile similar to other β-lactams [ 35 , 36 ]. Therefore, cefiderocol could be used in patients who are unable to tolerate polymyxins and other classes of antimicrobials. The broad range of GNB susceptible to cefiderocol and its relative safety profile mean it is a promising option for empirical therapy in immunocompromised patients. However, cefiderocol also demonstrates potency against specific difficult-to-treat GNB, including those that are CR. Cefiderocol could therefore be used as a broad-spectrum empirical therapy where antimicrobial resistance is suspected or likely, or could be used as a targeted treatment against MDR-GNB once resistance profiles are available. In conclusion, cefiderocol demonstrates high levels of activity against a wide range of GNB pathogens from multiple infection sources, including those resistant to meropenem. Cefiderocol was active against a range of isolates, including all classes of carbapenemase-producing Enterobacterales and MDR non-fermenters such as A. baumannii, P. aeruginosa, Burkholderia spp. and S. maltophilia , and is a potential therapeutic option for these organisms against which few other treatment options exist. Data access Data are available upon reasonable request from Shionogi & Co., Ltd. Acknowledgments The authors would like to thank all investigators and participating sites for the provision of clinical isolates. Co-ordination of the SIDERO-WT studies including generation of the in vitro MIC data and genetic sequencing of isolates was carried out by Meredith A. Hackel, Krystyna M. Kazmierczak and Daniel F. Sahm of International Health Management Associates, Inc. (IHMA) (Schaumburg, IL, USA), funded by Shionogi & Co., Ltd. (Osaka, Japan). Medical writing support was provided by Sarah Johnston, MBiolSci, of Ashfield Healthcare, part of UDG Healthcare plc, and was funded by Shionogi & Co., Ltd. Funding This work was supported by Shionogi & Co., Ltd. (Osaka, Japan). Competing interests EC has participated in educational meetings sponsored by MSD and Pfizer; CL is an employee of Shionogi; RP is a former employee of Shionogi; ASH is a contract employee of Shionogi; AP reports grants from MSD and grants and personal fees from Shionogi, outside of the submitted work. LC declares no competing interests. Ethical approval Not required; all in vitro samples were anonymised and no patient specimens were analysed, only bacterial isolates from routine diagnostic culture. 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