Search

Background Achromobacter spp. is intrinsically resistant to multiple antibiotics, and the treatment options are limited. Cefiderocol (CFDC), a siderophore cephalosporin approved in US and EU, is active against a wide variety of aerobic Gram-negative bacteria, including carbapenem-resistant strains. In this study, in vitro and in vivo antibacterial activity of CFDC against Achromobacter spp. was evaluated. Methods A total of 334 global isolates collected by IHMA from 39 countries in 2015-2019 were used. Minimum inhibitory concentrations (MICs) of CFDC and comparators were determined by broth microdilution method using iron-depleted CAMHB or CAMHB, respectively, as recommended by CLSI guidelines. In vivo efficacy of CFDC was compared with meropenem (MEM), piperacillin-tazobactam (PIP/TAZ), ceftazidime (CAZ), and ciprofloxacin (CIP) in a neutropenic murine lung infection model (n=5), and compared with MEM in a immunocompetent rat lung infection model (n=3-7) caused by 2 A. xylosoxydans. In the murine model, treatment was given 2, 5, and 8 hours post-infection, and the numbers of viable cfu in lungs were determined 24 hours post-infection. In the rat model, the humanized PK in plasma resulting from CFDC 2 g every 8 h (3-h infusion) or meropenem 1 g every 8 h (0.5-h infusion) were recreated via continuous intravenous infusion for 4 days, following which cfu in lungs were determined. Results CFDC showed in vitro activity with MIC50/90 of 0.06/0.5 µg/mL against 334 Achromobacter spp. Only 7 isolates (2.1%) had MICs > 4 µg/mL. These were the lowest values among all compound tested (Table). In the murine model, CFDC caused > 1.5 log10 decrease of viable cfu in lungs at 100 mg/kg dose (%fT >MIC: < 50%) from baseline control against both of strains (CFDC MIC: 0.5 and 2 µg/mL) (P< 0.05). No decrease of cfu in lungs was observed for the comparators at 100 mg/kg (MEM, PIP/TAZ, CAZ, and CIP MICs were >16, >64, >32, and >8 µg/mL, respectively). In the rat model, humanized CFDC dosing reduced the viable cfu by >1 log10 CFU/lung compared with baseline controls (P< 0.05). MEM showed no significant activity. In vitro activity of CFDC and comparator agents against Achromobacter spp. 334 Achromobacter spp. isolates collected from 2015 and 2019. The majority of isolates tested were A. xylosoxidans (312/334; 93.4%), followed by A. insolitus (11/334; 3.3%), Achromobacter sp. (8/334; 2.4%), A. denitrificans (2/334; 0.6%), and A. piechaudii (1/334; 0.3%). Conclusion CFDC showed potent in vivo efficacy reflecting in vitro activity against A. xylosoxidans. The results suggested that CFDC has the potential to be an effective therapeutic option for Achromobacter spp. infections. Disclosures Ryuichiro Nakai, MSc, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Ayaka makino, BSc, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Toriko Yoshitomi, -, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Rio Nakamura, BSc, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Meredith Hackel, PhD MPH, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Miki Takemura, MS, SHIONOGI & CO., LTD. (Employee) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Yoshinori Yamano, PhD, Shionogi (Employee)

ObjectivesMany carbapenem-resistant (CR) Gram-negative (GN) pathogens exhibit MDR, meaning few therapeutic options are available for CR-GN infections. Cefiderocol, a siderophore cephalosporin, has demonstrated in vitro efficacy against CR-GN bacteria. In the SIDERO-CR-2014–2016 surveillance study, European clinical isolates comprising carbapenem-non-susceptible (CarbNS) Enterobacterales and MDR non-fermenters were tested against cefiderocol and comparators.MethodsCefiderocol MICs were determined using iron-depleted CAMHB, and comparators using CAMHB, per recommended CLSI methodology. Carbapenemase gene profiles were determined using PCR.ResultsIsolates (N = 870) from 23 European countries comprised CarbNS Enterobacterales (n = 457), MDR Pseudomonas aeruginosa (n = 177) and MDR Acinetobacter baumannii (n = 236). The most common carbapenemases were KPC (52%), OXA-48-like (19%), VIM (14%) and NDM (8%) in Enterobacterales, VIM (41%) in P. aeruginosa and OXA-23-like (57%) and OXA-24/40-like (37%) in A. baumannii. Most carbapenemase-producing isolates (65%) co-carried ESBLs. Approximately half of P. aeruginosa isolates were negative for carbapenemases, compared with 10% of Enterobacterales and 3% of A. baumannii. A similar proportion of Enterobacterales were susceptible to cefiderocol (81.6%; 79.0% of VIM producers; 51.4% of NDM producers; based on EUCAST breakpoint values) compared with comparator antimicrobial agents, including colistin (76.4%; 93.5% of VIM producers; 78.4% of NDM producers) and ceftazidime/avibactam (76.6%; 1.6% of VIM producers; 2.7% of NDM producers). Of P. aeruginosa isolates, 98.3% were susceptible to cefiderocol (100% of VIM producers), similar to colistin (100%). Against A. baumannii, 94.9% had cefiderocol MIC ≤2 mg/L and 93.6% of isolates were susceptible to colistin.ConclusionsCefiderocol demonstrated potent activity against CarbNS and MDR GN bacteria, including non-fermenters and a wide variety of MBL- and serine-β-lactamase-producing strains.

Objectives The siderophore cephalosporin cefiderocol possesses in vitro activity against MDR Gram-negative bacteria. The stability of cefiderocol against serine- and metallo-type carbapenemases has been reported previously, but little is known about how cefiderocol interacts with chromosomal AmpC β-lactamases. We investigated a number of features of cefiderocol, namely antibacterial activity against AmpC overproducers, stability against AmpC β-lactamases and propensity for AmpC induction using Pseudomonas aeruginosa and Enterobacter cloacae. Methods MICs were determined by broth microdilution according to CLSI guidelines. The MIC of cefiderocol was determined in iron-depleted CAMHB. Hydrolysis of the antibiotics was determined by monitoring the changes in the absorbance in the presence of AmpC β-lactamase, and AmpC induction was evaluated by double disc diffusion and nitrocefin degradation assays. Results The MICs of ceftazidime and cefepime for PAO1 increased 4- to 16-fold with inactivation of either ampD or dacB, whereas cefiderocol MICs were little affected by these inactivations (

Background Cefiderocol (CFDC) is a novel siderophore cephalosporin with efficacy against Gram-negative (GN) bacteria, including carbapenem-resistant Enterobacterales and non-glucose-fermenters such as Pseudomonas aeruginosa and Acinetobacter baumannii. In consecutive multinational surveillance (SIDERO-WT) studies (2014–2017), CFDC demonstrated activity with minimum inhibitory concentrations (MICs) of ≤4 mg/mL against 99.4% of 28,629 GN clinical isolates. We conducted molecular characterization of 161 isolates with CFDC MICs >4 mg/mL from the SIDERO-WT studies. Methods A total of 161 isolates underwent whole genome sequencing by Illumina Hiseq. Analyses were done using the CLC genomics workbench (Qiagen) for possible resistance-related genes (e.g. β-lactamases, porin channels or penicillin-binding protein genes) and some TonB-dependent siderophore uptake receptor genes (fiu, cir, piu, pir). Fiu and Cir in Escherichia coli and Piu in P. aeruginosa are the iron transporters involved in CFDC transport. Results Of 161 isolates with CFDC MIC >4 mg/mL, 128 were A. baumannii, 22 Enterobacterales, 7 Burkholderia multivorans, 2 P. aeruginosa, and 2 Stenotrophomonas maltophilia. Genes encoding PER/VEB extended-spectrum β-lactamases and NDM-type metallo-β-lactamases were detected in some isolates, but other β-lactamase genes (bla) were not shown to be linked to high CFDC MICs. blaPER/blaVEB were found only in A. baumannii and blaNDM was found in A. baumannii and Klebsiella pneumoniae. In 128 A. baumannii isolates, 103 harbored PER or VEB, including PER positive isolates from Russia (n=87) and Turkey (n=6) and 4 VEB positive isolates from USA. Nine NDM-positive isolates (7 K. pneumoniae, 2 A. baumannii) were found. Disruption of iron transport genes was also detected in some isolates, including piuA (11 A. baumannii, 1 P. aeruginosa), pirA (2 A. baumannii), and fiuA (4 B. multivorans, 1 Proteus mirabilis). No cir homologs were found in 2 B. multivorans. Conclusion PER and NDM could reduce susceptibility to CFDC, as such isolates have been seen in some countries. Iron transporter disruption was also observed in some isolates with high CFDC MICs; the contribution of these deficiencies in A. baumannii and B. multivorans requires further study. Disclosures Yoshinori Yamano, PhD, Shionogi & Co., Ltd. (Employee) Miki Takemura, MSc, Shionogi & Co., Ltd. (Employee) Krystyna Kazmierczak, PhD, Shionogi & Co., Ltd. (Independent Contractor) Mark G G. Wise, PhD, Shionogi & Co., Ltd. (Independent Contractor) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Consultant)Shionogi & Co., Ltd. (Independent Contractor) Roger Echols, MD, Shionogi Inc. (Consultant)

Background Cefiderocol (CFDC) is a siderophore cephalosporin with broad coverage of aerobic Gram-negative (GN) bacteria. Provisional breakpoints (BP) were approved by CLSI in 2018, with FDA and EUCAST providing clinical BP in 2019 and 2020, respectively; however, BPs differ markedly between organizations, reflecting differences in labelling, PK/PD standards and availability of clinical study data during regulatory review. Here we compare susceptibility rates based on these different BPs. Methods Susceptibility rates for each bacterial species were determined using CFDC BP from each organization and the MICs of 28,629 GN clinical isolates from 3 consecutive years of SIDERO-WT surveillance studies (2014–17). The analysis used all isolates and sub-grouped isolates based on meropenem (MEM) susceptibility (CLSI BP) or carbapenemase production. Results Within the overall Enterobacterales group, ≥98.5% isolates were interpreted as susceptible to CFDC regardless of BP used. However, the proportion of susceptible differed significantly (82.5–98.6%) when applied to MEM-non-susceptible (NS) isolates. Similarly, against most carbapenemase producers, susceptibility ranged from 80 to 100%, however for NDM producers, only 51% of isolates were defined as susceptible by FDA or EUCAST BP vs 84% using the CLSI BP. Against Pseudomonas aeruginosa including MEM-NS isolates, susceptibility was ≥94% despite different BPs recommended by FDA (1 mg/L), EUCAST (2 mg/L) and CLSI (4 mg/L). This changed the proportion of IMP-producing isolates classified as susceptible from 100% (CLSI) and 81% (EUCAST) to only 19% (FDA). Against other non-fermenters, susceptibility was ≥91% irrespective of BP used. Table 1. Susceptibility rates against Enterobacterales based on breakpoints from each organization Table 2. Susceptibility rates against non-fermenters based on breakpoints from each organization Conclusion Differences in BPs between FDA, CLSI and EUCAST could impact on the reporting of susceptibility or resistance to CFDC, particularly for MEM-NS isolates. PK/PD model simulations support 100% fT >MIC up to an MIC of 4 mg/L, and in Phase 3 trials the mean trough concentration of unbound cefiderocol was >4 mg/L. The potential impact of these differences on clinical decision making are important as the greatest clinical utility for CDFC is expected to be in patients with carbapenem-resistant GN infections due to limited treatment options. Disclosures Yoshinori Yamano, PhD, Shionogi & Co., Ltd. (Employee) Miki Takemura, MSc, Shionogi & Co., Ltd. (Employee) Christopher Longshaw, PhD, Shionogi B.V. (Employee) Roger Echols, MD, Shionogi Inc. (Consultant)

Background DTR organisms are defined as nonsusceptible to all high-efficacy, low-toxicity antibiotics (penicillins, cephalosporins, carbapenems, and quinolones), leaving physicians with limited first-line treatment options. Analyses of electronic health records have shown that patients with DTR Gram-negative bacterial infections are more likely to receive inappropriate antibiotic therapy, have longer hospital stay and increased risk of mortality. CFDC is a novel parenteral siderophore cephalosporin with potent activity against aerobic Gram-negative pathogens, including carbapenem-resistant strains. We evaluated the in vitro activity of CFDC and comparators against DTR pathogens collected by the SIDERO-WT surveillance study. Methods A total of 30,459 clinical isolates of Gram-negative bacilli were systematically collected from United States, Canada, and 11 EU countries during 2014–2017. MICs were determined by broth microdilution for a panel of 7 antibiotics, including CFDC, ceftazidime–avibactam (CZA), ceftolozane–tazobactam (C/T), colistin (CST), cefepime (FEP), meropenem (MEM), and ciprofloxacin (CIP) according to CLSI guidelines. All antibiotics were tested in cation-adjusted Mueller–Hinton broth (CAMHB) except CFDC, for which iron-depleted CAMHB was used. Susceptibility was determined according to CLSI interpretive breakpoints except CST, where EUCAST breakpoints were used. DTR pathogens were defined as being nonsusceptible to FEP, MEM, and CIP according to CLSI breakpoints. Results Among 30,459 Gram-negative isolates collected between 2014 and 2017, 9.3% were nonsusceptible to FEP, MEM, and CIP and could be defined as DTR. DTR was most frequently observed in Acinetobacter spp. (55.5%), followed by Burkholderia spp. (19%), Pseudomonas aeruginosa (9.5%), and Enterobacterales (2.7%). Of the 1,173 Stenotrophomonas maltophilia tested, 97% had MEM MIC of ≥8 mg/L; however, only 2.9% could be defined as DTR. Cefiderocol was the most active antibiotic tested against DTR isolates with 94.5% DTR-Acinetobacter spp., 98.3% DTR-P. aeruginosa, and 99.8% DTR-Enterobacterales susceptible (Table 1). Conclusion CFDC demonstrated potent activity against DTR Gram-negative pathogens with limited first-line treatment options. Disclosures All authors: No reported disclosures.

Background Antibiotic susceptibility surveillance is the foundation for selecting treatment options as well as immediate and long-term strategies for combating antimicrobial resistance. We have conducted three surveillance studies SIDERO-WT-2014/-2015/-2016 with approximately 30,000 Gram-negative strains isolated in North America and Europe between 2014 and 2017. Here, we present the latest data of molecular analysis on acquired carbapenemase genes and antibiotic susceptibility of 3691 meropenem-nonsusceptible strains in the surveillance studies. Methods Meropenem-nonsusceptible strains isolated in North America (n = 1009) and Europe (n = 2,682), consisting of 1,897 Acinetobacter baumannii, 1,154 Pseudomonas aeruginosa, 447 Klebsiella pneumoniae, and 193 other Enterobacteriaceae were tested. Conventional PCR was used to detect known carbapenemases. Cefiderocol MICs were determined by broth microdilution method using iron-depleted cation-adjusted Mueller–Hinton broth. Results The percentages of known carbapenemases detected in 3 main pathogens are shown in the Table. In A. baumannii complex, OXA-23 was predominant followed by OXA-24 in most countries. The detection rates of VIM in P. aeruginosa were ≥40% in Greece and Russia, but none of the strains in the United States carried VIM. In K. pneumoniae, the predominant carbapenemase varied among the countries, with KPC predominating in the USA, Greece and Italy, while OXA-48-like was dominant in Russia, Spain and Turkey. Cefiderocol MIC90 were ≤4 μg/mL against these 3 pathogens in all 6 countries, except for A. baumannii strains in Russia. Conclusion Carbapenemase detection rates, especially in P. aeruginosa and K. pneumoniae, were quite different among the countries. Cefiderocol demonstrated potent in vitro activity against meropenem-nonsusceptible strains irrespective of the presence of specific carbapenemases. Disclosures All authors: No reported disclosures.

Background The global rise of carbapenem resistant Gram-negative bacteria such as carbapenem-resistant Enterobacteriaceae (CRE) and carbapenem-resistant non-fermenting bacteria is alarming and become threats to patient as only a few drugs remain active (e.g. colistin). Cefiderocol (S-649266) is a novel parenteral siderophore cephalosporin with potent activity against a wide variety of Gram-negative pathogens including carbapenem-resistant strains. This study evaluated the in vitro activity of cefiderocol and comparator agents against clinical isolates collected from urinary track source from North America. Methods A total of 3,323 Enterobacteriaceae, 263 Acinetobacter spp, 509 Pseudomonas aeruginosa, and 38 Stenotrophomonas maltophilia collected from the USA and Canada in 2014–2016 were tested. MIC was determined for cefiderocol, cefepime (FEP), ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C/T), ciprofloxacin (CIP), colistin (CST), and meropenem (MEM) by broth microdilution and interpreted according to CLSI 2016 guidelines. All testing was done at IHMA, Inc. As recommended by CLSI, cefiderocol was tested in iron-depleted cation-adjusted Mueller Hinton broth. Based upon CLSI breakpoints, carbapenem-non-susceptible (CarbNS) strains were defined as follows: MEM: MIC ≥2 µg/mL for Enterobacteriaceae, ≥4 µg/mL for non-fermenters. Quality control testing was performed on each day of testing by using E. coli ATCC25922 and P. aeruginosa ATCC27853. Results Cefiderocol exhibited in vitro activity against 4,133 strains of Gram-negative bacteria with an overall MIC90 of 0.5 µg/mL. At 4 µg/mL cefiderocol inhibited the growth of 99.9% of the all isolates. MIC90 of cefiderocol against CarbNS Enterobacteriaceae was 4 µg/mL although MIC90 of other comparators were >64 or >8 (CST) µg/mL. The cefiderocol MIC90value was 1 µg/mL for CarbNS non-fermeneters. Conclusion Cefiderocol demonstrated potent in vitro activity against Enterobacteriaceae, A. baumannii, P. aeruginosa, and S. maltophilia isolates collected from a UTI source, with greater than 99.9% of isolates having MIC values ≤4 µg/mL. These findings indicate that this agent has high potential for treating cUTI infections caused by these problematic organisms, including isolates resistant to colistin. Disclosures M. Tsuji, Shionogi & Co.: Employee, Salary; M. Hackel, IHMA: Employee, Salary; R. Echols, Shionogi & CO., LTD: Consultant, Consulting fee; Y. Yamano, Shionogi & Co.: Employee, Salary

Background Cefiderocol (S-649266, CFDC) is a novel siderophore cephalosporin against Gram-negatives, including carbapenem (CR)-resistant strains. Its spectrum includes both the Enterobacteriaceae but also nonfermenters, including Stenotrophomonas maltophilia—an opportunistic pathogen with intrinsic resistance to carbapenem antibiotics. In this study, in vitro activity and in vivo efficacy of CFDC and comparators against S. maltophilia were determined. Methods MICs of CFDC and comparators (trimethoprim/sulfamethoxazole (TMP/SMX), minocycline (MINO), tigecycline (TGC), ciprofloxacin (CPFX), cefepime (CFPM), meropenem (MEPM), and colistin (CL)) were determined by broth microdilution method as recommended by CLSI. The MIC against CFDC was determined using iron-depleted cation-adjusted Mueller–Hinton broth. In vivo efficacy of CFDC, CFPM, ceftazidime–avibactam (CAZ/AVI), MEPM, and CL was evaluated using neutropenic murine systemic infection model caused by strain SR21970. The 50% effective doses (ED50s) were calculated by the logit method using the survival number at each dose 7 days after infection. Results MIC90 of CFDC and comparators against the 216 clinical isolates from global countries collected in SIDERO-CR 2014/2016 study are shown in the table. CFDC, TMP/SMX, MINO, and TGC showed good activity with MIC90 of 0.5, 0.25/4.75, 1, and 2 µg/mL, respectively. CFDC, MINO, and TGC inhibited growth of all tested strains at ≤1, ≤4, and ≤8 µg/mL although two strains showed resistance to TMP/SMX. MICs of CFPM, CAZ/AVI, MEPM, and CL were ≥32 µg/mL. The ED50 of CFDC against S. maltophilia SR21970 with MIC of 0.125 mg/mL was 1.17 mg/kg/dose. Conversely, MICs of CFPM, CAZ/AVI, MEPM/CS, and CL against SR21970 were 32 μg/mL or higher, and ED50s were >100 mg/kg/dose, showing that CFDC had potent in vivo efficacy against S. maltophilia strain which was resistant to other antibiotics. Conclusion CFDC showed potent in vitro activity against S. maltophilia, including TMP/SMX-resistant isolates. CFDC also showed potent in vivo efficacy reflecting in vitro activity against S. maltophilia in murine systemic infection model. Disclosures A. Ito, Shionogi & Co., Ltd.: Employee, Salary. M. Ota, Shionogi & Co., Ltd.: Employee, Salary. R. Nakamura, Shionogi & Co., Ltd.: Employee, Salary. M. Tsuji, Shionogi & Co., Ltd.: Employee, Salary. T. Sato, Shionogi & Co., Ltd.: Employee, Salary. Y. Yamano, Shionogi & Co., Ltd.: Employee, Salary.

Background Previous pharmacodynamic (PD) assessments conducted over a 24 hours dosing period have revealed that cefiderocol humanized exposures produced predictable bacterial kill against MDR Gram-negatives with MICs ≤4 mg/L. Our current aim was to evaluate the sustainability of cefiderocol in vivo activity over 72 hours against MDR pathogens. A. baumannii (AB, n = 4), P. aeruginosa (PSA, n = 2), K. pneumoniae (KP, n = 4) and E. coli (EC, n = 2) displaying cefiderocol MICs of 0.5–16 mg/L were used in the neutropenic murine thigh model. Methods Mice received either humanized exposures of cefiderocol equivalent to the clinical dose [2g q8h 3h inf.] or cefepime (FEP) reflective of a 2g q8h 3h inf or vehicle. Efficacy was determined as the change in log CFU at 24, 48 and 72h compared with 0 hours controls. MICs were determined on organisms recovered from both the control and treatment animals. Results In AB, PSA and Enterobacteriaceae (EB) displaying MICs 0.5–8 (n = 9), infected mice given cefiderocol showed reductions of 0.5–3 log CFU at 72 hours. The killing profile observed among these 9 isolates followed a similar trend, demonstrating an initial reduction in bacterial burden at 24 hours which was sustained at 48 hours and 72 hours. As expected based on the PD profile of cefiderocol, no killing was seen with the AB isolate (MIC = 16). While cefiderocol exposure resulted in the killing of the FEP-resistant phenotype of the EB, mice receiving FEP displayed growth similar to controls. Infection with the remaining 2 organisms (EC 462, MIC = 1; KP 531, MIC = 4) resulted in a cumulative increase in bacterial burden over the study duration resulting in 1–2 logs growth following cefiderocol exposure over 72 hours. Retest MICs revealed an increase (≥2 dilutions) compared with control in only 1 animal (1/54 samples or 1.8%) observed in EC 462 at 72 hours. Additional samples from this group (2/3) remained unchanged throughout the study duration. Importantly, the retest MIC for this sample did not exceed the MIC of 4 mg/L. Conclusion These data show that for isolates demonstrating kill at 24 hours, cefiderocol efficacy was unchanged over the 72 hours treatment period. Despite the MDR profile of the pathogens tested their phenotypic profile remained largely unchanged and adaptive resistance during therapy was not observed. Disclosures M. Tsuji, Shionogi & Co., Ltd.: Employee, Salary. Y. Yamano, Shionogi & Co., Ltd.: Employee, Salary.