Iron-depleted Cation-adjusted Mueller-Hinton Broth Research Articles

P-1099. Correlation Analysis of Cefiderocol In vitro Activity and In vivo Efficacy Against Acinetobacter baumannii Strains with Difficult-to-Read MIC Endpoints

Abstract Background Cefiderocol (FDC) is a siderophore-conjugated cephalosporin with broad activity against Gram-negative bacteria, including Acinetobacter baumannii. For some isolates, determining the minimum inhibitory concentration (MIC) endpoints for FDC can be difficult due to the trailing growth phenomenon. Recently guidance on how to determine the MIC when trailing occurs has been updated in the CLSI M100 document, to enhance MIC reproducibility. In this study, we determined MICs of A. baumannii strains that show difficult to determine MIC endpoint due to trailing according to the updated CLSI guidance and analyzed correlations between MICs and in vivo efficacy. In vivo bacterial growth or reduction from start of treatment with cefiderocol against Acinetobacter baumannii in the neutropenic murine thigh infection model using humanized pharmacokinetic exposure of cefiderocol. In vivo (S): mean of reduction in bacterial cell number at 24 hours after initial treatment with cefiderocol (mean of change <0 log10 colony forming unit (CFU) /thigh) CFU/thigh), in vivo (R): mean of increase in bacterial cell number at 24 hours after initial treatment with cefiderocol (mean of change ≥0 log10 CFU/thigh). MIC values shown blue, orange, and red indicate susceptible, intermediate, and resistant, respectively, according to CLSI guideline 2024. Methods MICs were determined according to the 2024 CLSI guidance using iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) from BD-BBL for 43 A. baumannii isolates, including 13 strains that show severe trailing. All strains had been evaluated in vivo in the murine thigh infection model using humanized pharmacokinetic exposure of FDC (1). Categorical agreements between MICs and in vivo efficacy in murine thigh infection model Susceptible (S), Non-susceptible (NS), breakpoints as published by CLSI (2024), In vivo (S): mean of reduction in bacterial cell number at 24 hours after initial treatment with cefiderocol (mean of change <0 log10 colony forming unit (CFU)/thigh, in vivo (R): mean of increase in bacterial cell number at 24 hours after initial treatment with cefiderocol (mean of change ≥0 log10 CFU/thigh). Results FDC MIC range of tested A. baumannii strains was 0.12 to >32 μg/mL. Among 19 strains that showed a reduction in bacterial load after treatment with FDC in the murine thigh infection model, 94.7% (18/19 strains) were categorized as FDC susceptible (Figure and Table 1). Among 24 strains that showed increase in bacterial load after treatment with FDC in vivo, 87.5% (21/24 strains) were categorized as FDC non-susceptible. The categorical agreement of MICs and in vivo efficacy was 90.7% (39/43). As for the 13 strains that showed severe trailing, the categorical agreement of MICs and in vivo efficacy was 84.6% (11/13, Table 2). The updated CLSI guidance did not impact the overall agreement that was obtained earlier using the previous CLSI guidance (Table 1, 2). Categorical agreements between MICs and in vivo efficacy in murine thigh infection model for 13 strains that showed severe trailing Susceptible (S), Non-susceptible (NS), breakpoints as published by CLSI (2024), In vivo (S): mean of reduction in bacterial cell number at 24 hours after initial treatment with cefiderocol (mean of change <0 log10 colony forming unit (CFU)/thigh, in vivo (R): mean of increase in bacterial cell number at 24 hours after initial treatment with cefiderocol (mean of change ≥0 log10 CFU/thigh). Conclusion Our correlation analysis between MICs and in vivo efficacy in thigh infection model confirms the validity of MIC endpoint determinations described in CLSI M100 document, including strains that show severe trailing. Reference: 1. Monogue L, et al. Antimicrob Agents Chemother. 2017;61(11):e01022-17. Disclosures Hidenori Yamashiro, Shionogi & Co., Ltd.: Employee Motoyasu Onishi, PhD, Shionogi & Co., Ltd.: Employee Naomi Anan, MSc, Shionogi & Co., Ltd.: Employee Boudewijn L. DeJonge, PhD, Shionogi Inc.: Employee Christopher M. Longshaw, PhD, Shionogi BV: Employee Miki Takemura, n/a, Shionogi & Co., Ltd.: Employee Yoshinori Yamano, PhD, Shionogi & Co., Ltd.: Employee

P-1370. Molecular Bases and Mechanistic Insights of NDM-mediated Resistance to Cefiderocol

Abstract Background Cefiderocol (FDC) is a novel cephalosporin with a siderophore-mimicking moiety that favors uptake into the periplasm through iron transporters. FDC was reported as the only cephalosporin refractory to hydrolysis by metallo-β-Lactamases (MBLs). However, resistance to FDC has been reported due to substitutions in the iron transporter coupled to the expression of the MBLs NDM-1 and NDM-5. In contrast, resistance emergence involving other MBLs such as VIM or IMP are not known. We aimed to identify the interaction of FDC with NDM and other MBLs.Table 1.Kinetic parameters of FDC hydrolysis by different MBLsNDM variants show considerable activity in FDC hydrolysis. In contrast, VIM-2 and IMP-1 show poor activity. Methods MICs values of FDC against Escherichia coli DH10B cells expressing different MBLs cloned into a pHSG298 vector were determined by the microdilution method in iron-depleted cation-adjusted Mueller-Hinton broth. NDM-1, NDM-5, IMP-1 and VIM-2 were expressed in E. coli BL21(DE3) pLysS and purified by affinity chromatography. Steady state catalytic parameters were determined by initial rate measurements measured in HEPES buffer, pH 7.5 at 25°C. NMR spectra were run in a 700 MHz Bruker spectrometer. Stopped-flow data were acquired in an Applied Photophysics spectrophotometer. Mechanism of MBL-mediated resistance to FDC Under high levels of NDM expression, the enzymatic activity counter the cefiderocol action, confering bacterial resistance against this antibiotic. Results MIC values of FDC in E. coli cells expressing NDM variants were 2 μg/ml, similar to NDM-1. Steady-state kinetic measurements showed that NDM-1 and NDM-5 hydrolyze FDC efficiently, with kcat/KM values of 1.9 and 1.2 x10^6 M-1s-1, respectively. In contrast, IMP-1 and VIM-2 displayed poor catalytic efficiencies (Table 1). Electrospray ionization mass spectrometry (ESI-MS) revealed that FDC forms an adduct with MBLs, which is significantly more stable in the case of IMP-1 and VIM-2. Stopped flow experiments under pre-steady state conditions show that both IMP-1 and VIM-2 form a stable adduct with FDC, that results in enzyme inhibition. Instead, NDM-1 is poorly inhibited since the formed adduct is less stable. NMR experiments confirmed the formation of an hydrolysis product and adduct. Conclusion Our results indicate that NDM-1 and NDM-5 hydrolyze FDC efficiently, in contrast to the poor activity of IMP-1 and VIM-2. These findings support the observation that clinical resistance is linked to overexpression of NDM variants and not to IMP-1 and VIM-2. This may guide the use of FDC against a specific group of MBLs and justifies pairing with an MBL inhibitor. Disclosures All Authors: No reported disclosures

P-1100. Activity of Cefiderocol and Comparator Agents Against Global Isolates of Stenotrophomonas maltophilia from the SENTRY Antimicrobial Surveillance Program (2020–2023)

Abstract Background Stenotrophomonas maltophilia is a ubiquitous multidrug-resistant opportunistic pathogen. Infections caused by S. maltophilia have limited antibiotics treatment options due to the intrinsic resistant mechanisms such as the production of chromosomal L1 metallo-type carbapenemase and L2 extended-spectrum type β-lactamase. Cefiderocol (FDC) is a siderophore-conjugated cephalosporin with broad activity against Gram-negative bacteria, including S. maltophilia. In this study, the in vitro activities of cefiderocol and comparators were investigated against S. maltophilia clinical isolates that were collected from the US and Europe in 2020-2023 as part of the SENTRY Antimicrobial Surveillance Program. Susceptibility of Stenotrophomonas maltophilia to cefiderocol and comparator agents Cefiderocol (FDC), levofloxacin (LVFX), trimethoprim-sulfamethoxazole (TMP-SMX), minocycline (MIN), ceftazidime (CAZ), imipenem-relebactam (I/R), ceftazidime-avibactam (CZA), non-susceptible (NS), susceptible (S), intermediate (I), resistant (R), N/A (not applicable), a cefiderocol S ≤1, levofloxacin S ≤2, trimethoprim-sulfamethoxazole S ≤2/38, minocycline S ≤1, breakpoints as published by CLSI (2024), b cefiderocol S ≤2, levofloxacin S ≤0.5, ceftazidime S≤4, imipenem-relebactam S ≤2, ceftazidime-avibactam S ≤8, PK-PD breakpoints as published by EUCAST (2023) Methods A total of 1782 S. maltophilia isolates were consecutively collected from the US and Europe from 2020-2023. The most common infection type from which isolates were collected was pneumonia (n=1193), followed by skin and skin structure (n=166), bloodstream infection (n=208), and urinary tract infections (n=56). Minimum inhibitory concentrations (MICs) of FDC and comparators were determined by using iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) for cefiderocol and CAMHB for comparators. MIC50, MIC90, and MIC range were calculated. Susceptibility rates were determined by using CLSI breakpoints (2024) and EUCAST PK-PD breakpoints (2023). Results FDC was the most potent agent tested against S. maltophilia, showing the lowest MIC90 value of 0.25 µg/mL (Table). The MIC90 values of levofloxacin (LVFX), trimethoprim-sulfamethoxazole (TMP-SMX), and minocycline (MIN) were 4, 0.5, and 1 µg/mL, respectively. The MIC90 values of other comparator agents were >8 µg/mL. Susceptibilities of FDC, LVFX, SMT, and MIN were 99.3, 83.0, 97.0, and 93,0%, respectively. The susceptibility to FDC was the highest against LVFX-, TMP-SMX- or MIN-non-susceptible isolates according to both CLSI and EUCAST breakpoint (Table). Conclusion FDC showed potent in vitro activity against S. maltophilia collected in the US and Europe from 2020-2023, including isolates non-susceptible to LVFX, TMP-SMX, or MIN, suggesting that FDC is an important therapeutic option for S. maltophilia infections. Disclosures Motoyasu Onishi, PhD, Shionogi & Co., Ltd.: Employee Hidenori Yamashiro, Shionogi & Co., Ltd.: Employee Rodrigo E. Mendes, PhD, GSK: Grant/Research Support Boudewijn L. DeJonge, PhD, Shionogi Inc.: Employee Sean T. Nguyen, PharmD, Shionogi Inc.: Employee Christopher M. Longshaw, PhD, Shionogi BV: Employee Miki Takemura, n/a, Shionogi & Co., Ltd.: Employee Yoshinori Yamano, PhD, Shionogi & Co., Ltd.: Employee

P-1360. Activity of Cefiderocol against Carbapenem Non-susceptible Enterobacterales, Including Molecularly Characterized Multidrug-resistant Clinical Isolates, Causing Infections in United States Hospitals (2020–2023)

Abstract Background Cefiderocol (FDC) is a siderophore cephalosporin that hijacks the iron transport system of Gram-negative bacteria to facilitate cell entry. FDC remains stable to hydrolysis in the presence of serine β-lactamases (BL) (e.g. ESBLs, KPC, and OXA-type carbapenemases) and metallo-BL (MBL). FDC and comparator activities were analyzed against carbapenem-nonsusceptible (nonS) Enterobacterales (ENT), including molecularly characterized isolates, collected as part of the SENTRY Antimicrobial Surveillance Program for the US. Methods 15,147 ENT were collected from 35 sites in 2020–2023. Susceptibility (S) testing was performed by broth microdilution with cation-adjusted Mueller-Hinton broth (CAMHB) for comparators and iron-depleted CAMHB for FDC. CLSI criteria (same as the FDA) were used for FDC; whereas CLSI were applied for comparators, except for colistin (EUCAST). ENT with MIC ≥2 mg/L (nonS by CLSI) for imipenem or meropenem (MER) were screened for BL genes. Results 1.4% (207/15,147) isolates were carbapenems-nonS, and among these 57.5% (119/207) carried carbapenemases. Class A blaKPC (72.3%; 86/119) prevailed, followed by class B MBL genes (17.6%; 21/119) and class D blaOXA-48 variants (5.9%; 7/119). FDC (96.6–98.3%S) had MIC50 of 0.5 mg/L and MIC90 of 4 mg/L against carbapenem-nonS and carbapenemase-carrying isolates; other agents had S of 6.7–86.5% (Table). FDC (100%S) and β-lactam-β-lactamase inhibitor (BL/BLI) combinations (96.6–100%S) were active against ENT carrying class A carbapenemases, whereas only FDC (MIC50/90, 2/4 mg/L; 95.2%S) had activity against those carrying class B genes. FDC and ceftazidime-avibactam (CAZ-AVI) were active (100%S for both) against ENT carrying class D genes. FDC (MIC50/90, 0.25/4 mg/L; 92.1%S), MER-vaborbactam (MIC50/90, 0.25/4 mg/L; 92.1%S) and CAZ-AVI (MIC50/90, 0.5/8 mg/L; 94.7%S) were most active against carbapenem-nonS, but carbapenemase-negative ENT. Conclusion FDC activity against carbapenem-nonS ENT collected in the US. FDC activity was consistent across different genotypes, including against isolates carrying carbapenemase genes, where approved BL/BLI combinations showed limited activity. These data demonstrate FDC as an important option for the treatment of infections caused by carbapenem-nonS ENT. Disclosures Rodrigo E. Mendes, PhD, GSK: Grant/Research Support

P-1364. Cefiderocol Activity against Pseudomonas aeruginosa Clinical Isolates Carrying Metallo-β-lactamase Genes in United States and European Hospitals (2020–2023)

Abstract Background Cefiderocol (FDC) is a siderophore cephalosporin that uses the iron transport systems of Gram-negative bacteria to optimize cell entry. FDC is stable to hydrolysis by serine and metallo-β-lactamases (MBL). FDC and comparator activities were analyzed against P. aeruginosa (PSA) carrying MBL genes, as part of the SENTRY Antimicrobial Surveillance Program. Methods 9,573 PSA were collected from 36 sites in the US and 43 sites in Europe (EU) in 2020–2023. Susceptibility (S) testing used broth microdilution with cation-adjusted Mueller-Hinton broth (CAMHB) for comparators and iron-depleted CAMHB for FDC. CLSI/EUCAST breakpoints were used for FDC; whereas CLSI were applied for comparators (EUCAST for colistin [COL]). Isolates with MIC ≥4 mg/L (nonS by CLSI) for imipenem or meropenem were screened for β-lactamase genes. Results Carbapenem-nonS PSA comprised 23.4% (2,236/9,573) of isolates, with 22.3% (980/4,400) and 24.3% (1,256/5,173) originating from US and EU sites, respectively (Table). 5.5% (124/2,236) of PSA carried MBL, and these PSA were mostly from EU (94.4%). FDC (98.3–99.4%S) had MIC50 of 0.12 mg/L and MIC90 of 0.5 mg/L against carbapenem-nonS PSA from the US and EU, whereas other agents had lower S (80.9–90.2%), except for COL (99.7–99.8%S). Aztreonam-avibactam inhibited only 48.4% and 57.6% of carbapenem-nonS PSA from the US and EU at MIC of ≤8 mg/L, respectively. FDC (MIC50/90, 0.25/2 mg/L; 94.4–96.0%S) had activity against the MBL-carrying PSA subset; in contrast, other agents had off-scale MIC90 (i.e. >8 mg/L), except for COL (100%S). All PSA carrying blaIMP and blaVIM were susceptible to FDC (MIC90/100, 1/2 mg/L), whereas higher FDC MIC (MIC50/90, 2/16 mg/L; 57.1–64.3%S) were noted against blaNDM-carrying PSA. Conclusion FDC showed potent activity against carbapenem-nonS PSA clinical isolates from US and EU hospitals, including isolates carrying MBL genes, whereas newly launched BL/BLI didn’t show activity. FDC should be considered as an important option for the treatment of infections caused by these resistant subsets for which antibiotic treatment option are limited. Disclosures Rodrigo E. Mendes, PhD, GSK: Grant/Research Support

P-1363. Cefiderocol Activity against Clinical Enterobacterales Isolates Carrying Metallo-β-lactamase Genes in United States and European Hospitals (2020–2023)

Abstract Background Cefiderocol (FDC) is a siderophore cephalosporin that uses the iron transport systems of Gram-negative bacteria to optimize cell entry. FDC is stable to hydrolysis by serine (e.g. ESBLs, KPC, and OXA-type carbapenemases) and metallo-β-lactamases (MBL). FDC and comparator activities were analyzed against Enterobacterales (ENT) carrying MBL genes, as part of the SENTRY Antimicrobial Surveillance Program. Methods 32,052 ENT were collected from 35 sites in the US and 42 sites in the European (EU) regions during 2020–2023. Susceptibility (S) testing used broth microdilution with cation-adjusted Mueller-Hinton broth (CAMHB) for comparators and iron-depleted CAMHB for FDC. CLSI (same as the FDA) breakpoints were used for FDC; whereas CLSI were applied for comparators, except for colistin (EUCAST). ENT with MIC ≥2 mg/L (nonS based on CLSI criteria) for imipenem or meropenem were screened for β-lactamase genes. Results Carbapenem-nonS isolates comprised 2.9% (944/32,052) of the population, of which 1.4% (207/15,147) and 4.4% (737/16,905) originated from US and EU sites, respectively. FDC (94.6–96.6%S) had equivalent MIC90 of 4 mg/L against all carbapenem-nonS isolates, and the US and EU subsets, whereas other agents had S ≤86.5% (Table). FDC had MIC50/90 of 2/4 mg/L against isolates carrying MBL genes, including the blaNDM and blaVIM-1 subsets; in contrast, various other agents had off-scale MIC90 values (i.e. >8 mg/L). FDC MIC90 of 8 mg/L were obtained against isolates carrying blaNDM-5. Conclusion FDC showed potent activity against carbapenem-nonS ENT and those subsets of isolates carrying MBL genes. This potent FDC activity is presented against a particular subset of resistant ENT, for which antibiotic treatment options are limited. FDC should be considered as an important option for the treatment of infections caused by these resistant organisms. Disclosures Rodrigo E. Mendes, PhD, GSK: Grant/Research Support

P-1484. In vitro Activity of Cefiderocol and Comparator Agents Against Non-fermentative Gram-negative Bacilli Isolated from Patients Hospitalized with Pneumonia as part of the SENTRY Global Surveillance Program (2020-2022)

Abstract Background Cefiderocol (CFDC) is a siderophore-conjugated cephalosporin with broad activity against Gram-negative bacteria including non-fermenters resistant to carbapenems. The in vitro activity of CFDC and comparators was evaluated against glucose non-fermenting Gram-negative bacteria isolated from patients hospitalized with pneumonia.Table 1:Activity of cefiderocol and comparator agents against Pseudomonas aeruginosa, Acinetobacter baumannii-calcoaceticus complex, and Stenotrophomonas maltophilia isolates from patients hospitalized with pneumonia from 2020-2022 Methods 5,995 isolates were collected between 2020-2022 from pneumonia patients as part of the global SENTRY Antimicrobial Surveillance Program, including: 3,809 Pseudomonas aeruginosa (PSA), 1,092 Acinetobacter baumannii-calcoaceticus complex (ABC), 808 Stenotrophomonas maltophilia (STM), 104 Achromobacter spp. (ACHR), 81 Burkholderia cepacia complex (BURK), and 101 other isolates. Minimum inhibitory concentrations (MIC) were assessed by CLSI guidelines using broth microdilution with cation-adjusted Mueller-Hinton broth (CAMHB) for comparators and iron-depleted CAMHB for CFDC. Susceptibility was assessed according to 2024 CLSI, FDA, and EUCAST breakpoints. Carbapenem resistance (CR) was defined as resistant to meropenem and imipenem by CLSI breakpoints. Results Against PSA, CFDC and β-lactam/β-lactamase inhibitor combinations all had susceptibility >95%. However only CFDC maintained high susceptibility against CR-PSA with 99.3% of the isolates being susceptible by CLSI breakpoints. No other comparator had > 90% susceptibility against CR-PSA (Table 1). Against ABC, CFDC demonstrated 97.5% susceptibility by CLSI breakpoints. This high susceptibility was maintained against CR-ABC with 96.1% susceptibility using CLSI breakpoints. Colistin showed 75.5% susceptibility per EUCAST breakpoint, but ceftazidime and ampicillin-sulbactam had no appreciable activity. CFDC, trimethoprim-sulfamethoxazole, and minocycline all showed >90% susceptibility against STM. Against ACHR and BURK, CFDC had high activity, with MIC50/90 values of 0.03/0.5 and 0.06/1 mg/L, respectively. Conclusion CFDC demonstrated high in vitro activity against glucose non-fermenters isolated from hospitalized patients with pneumonia. In particular, CFDC maintained high susceptibility against CR isolates making it an important treatment option for pneumonia patients at risk of infection with a CR non-fermenter. Disclosures Frank Kung, PhD, Shionogi Inc: Employee Sean T. Nguyen, PharmD, Shionogi Inc.: Employee Boudewijn L. DeJonge, PhD, Shionogi Inc.: Employee Christopher M. Longshaw, PhD, Shionogi BV: Employee Jason J. Bryowsky, PharmD, MS, Shionogi: Employee Rodrigo E. Mendes, PhD, GSK: Grant/Research Support Miki Takemura, n/a, Shionogi & Co., Ltd.: Employee Yoshinori Yamano, PhD, Shionogi & Co., Ltd.: Employee

P-1362. Cefiderocol Activity against Carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex, Including Molecularly Characterized Clinical Isolates, Causing Infections in United States Hospitals (2020–2023)

Abstract Background Multidrug-resistant (MDR) Acinetobacter baumannii-calcoaceticus complex (ACB) have gained attention as an important clinical challenge in the last decades, due to its ability to develop resistance to front-line antibiotics. Cefiderocol (FDC) is a siderophore cephalosporin that uses the iron transport systems of Gram-negative bacteria to optimize cell entry. The activity of FDC and comparators were evaluated against ACB causing infections in US hospitals, including resistant subsets, collected as part of the SENTRY Antimicrobial Surveillance Program. Methods 1,786 Acinetobacter spp. were collected from 36 sites in the US during 2020–2023. Susceptibility (S) testing was performed by broth microdilution with cation-adjusted Mueller-Hinton broth (CAMHB) for comparators and iron-depleted CAMHB for FDC. CLSI/EUCAST/FDA criteria were applied. Isolates with imipenem or meropenem MIC ≥4 mg/L (nonS by CLSI) were screened for β-lactamase genes. Results ACB comprised 80.5% (1,438/1,786) of isolates collected, and all 405 carbapenem-nonS isolates were identified as ACB. Carbapenemase genes were detected in 86.9% (352/405) of carbapenem-nonS ACB, and blaOXA-23 (59.9%; 211/352) prevailed, followed by blaOXA-24 (25.6%; 90/352), and blaOXA-72 (9.4%; 33/352). FDC (93.6–98.8%S) had MIC50 of 0.12 mg/L and MIC90 of 1 mg/L against all Acinetobacter spp. and the ACB subset (Table). Comparators had limited activity against these isolates (66.5–77.1%S), except for colistin (COL) (95.7–96.2%S). FDC (97.0–97.7%S by CLSI) had MIC50 of 0.25 mg/L and MIC90 of 2 mg/L against carbapenem-nonS ACB and those carrying carbapenemases. Only COL was also active against these 2 resistant subsets. FDC (97.2–100%S by CLSI) MIC90 of 2 mg/L, 1 mg/L and 0.5 mg/L were obtained against ACB carrying blaOXA-23, blaOXA-24, and blaOXA-72, respectively. Isolates carrying other carbapenemases were inhibited by FDC MIC of ≤2 mg/L, except for 1 strain with blaOXA-23 and blaNDM-1 (MIC, 8 mg/L). Conclusion This study demonstrates the MDR nature of ACB causing infections in US hospitals, and FDC as an active agent against these isolates, regardless of resistance genotype. These in vitro data suggest FDC as an important option for the treatment of infections caused by MDR ACB. Disclosures Rodrigo E. Mendes, PhD, GSK: Grant/Research Support

P-1530. Evaluation of Phenotypic Cross-Resistance between Cefiderocol and β-lactam/β-lactamase inhibitor combinations against Pseudomonas aeruginosa isolates from US Medical Centers

Abstract Background Prevalence of multi-drug resistant P. aeruginosa isolates has been increasing with cross-resistance reported among β-lactam/β-lactamase inhibitor (BL/BLI) combinations. This study evaluates cross-resistance between anti-pseudomonal BL/BLI combinations and cefiderocol (CFDC) against various non-susceptible (NS) subsets of P. aeruginosa isolates collected from US hospitals participating in the SENTRY surveillance program. Susceptibility of cefiderocol (CFDC), ceftazidime/avibactam (CZA), ceftolozane/tazobactam (C/T), and imipenem/relebactam (I/R) against various non-susceptible subsets of P. aeruginosa isolates from US hospitals participating in the SENTRY surveillance program during 2020-2022 Methods A total of 3,384 clinical P. aeruginosa isolates were collected between 2020-2022 from hospitalized patients in 34 US hospitals as part of the SENTRY Antimicrobial Surveillance Program. Minimum inhibitory concentrations were determined according to CLSI guidelines using broth microdilution with cation-adjusted Mueller-Hinton broth (CAMHB) for comparator agents and iron-depleted CAMHB for CFDC. Susceptibility was assessed according to 2024 CLSI and FDA breakpoints. Carbapenem-non-susceptible (CarbNS) was defined as non-susceptibility to meropenem and imipenem. Results Cross-resistance was observed among ceftazidime/avibactam (CZA), ceftolozane/tazobactam (C/T), and imipenem/relebactam (I/R). Of the C/T-NS P. aeruginosa isolates, only 37.2% of isolates and 62.8% of isolates were susceptible to CZA and I/R, respectively. In CZA-NS isolates, 53.8 % and 65.8 % tested as susceptible for C/T and I/R. Among I/R-NS P. aeruginosa isolates, 54.5 % and 63.6 % tested as susceptible for CZA and C/T, respectively. BL/BLI cross-resistance does not appear to affect susceptibility to CFDC, as >80% and ≥93% of CZA-NS, C/T-NS, and I/R-NS isolates tested as susceptible according to FDA and CLSI breakpoints, respectively. In various BL/BLI-NS ± CarbNS phenotypes, CFDC susceptibility was >88 % (CLSI breakpoints) while the various BL/BLI combinations susceptibilities ranged from 0-64.4 %. CFDC-NS was rare (< 1%), and none of these isolates were susceptible to CZA or C/T. Conclusion In clinical isolates derived from US hospitalized patients, CFDC was highly active against P. aeruginosa NS isolates to BL/BLI combinations, whereas cross-resistance was observed amongst these combinations. The data supports the use of CFDC as an important treatment option against P. aeruginosa NS to BL/BLI combinations. Disclosures Sean T. Nguyen, PharmD, Shionogi Inc.: Employee Boudewijn L. DeJonge, PhD, Shionogi Inc.: Employee Jason J. Bryowsky, PharmD, MS, Shionogi: Employee Rodrigo Mendes, PhD, Shionogi & Co., Ltd.: Grant/Research Support Miki Takemura, n/a, Shionogi & Co., Ltd.: Employee Yoshinori Yamano, PhD, Shionogi & Co., Ltd.: Employee

P-1472. Cefiderocol Remains Highly Active Against Carbapenemase-Producing Enterobacterales

Abstract Background Carbapenem-resistance in Enterobacterales is mediated by the acquisition of β-lactamases, including serine carbapenemases (KPC and OXA-48) and metallo-β-lactamases (NDM, IMP and VIM). Cefiderocol (CFDC) is a siderophore conjugated cephalosporin with good stability against all classes of β-lactamases. In this study, in vitro activity for CFDC and comparator agents was assessed against meropenem and/or imipenem non-susceptible carbapenemase-producing (CP) isolates that were collected between 2020-2022 in Europe and the USA as part of the SENTRY Antimicrobial Surveillance Program.Table 1.Susceptibility for cefiderocol and comparator agents against meropenem and/or imipenem non-susceptible carbapenemase-producing Enterobacterales isolates collected from European and US hospitals as part of the SENTRY surveillance program during 2020-2022. Methods A total of 24,084 Enterobacterales were collected and minimum inhibitory concentrations (MIC) for compactor agents were determined according to CLSI guidelines using broth microdilution with cation-adjusted Mueller-Hinton broth (CAMHB), while for CFDC iron-depleted CAMHB was used. Susceptibility was assessed according to 2024 CLSI, FDA, and EUCAST breakpoints. Isolates non-susceptible for meropenem and/or imipenem, based on CLSI breakpoints (n=2,029), were subjected to whole genome sequencing to determine their carbapenemase content. Results 474 isolates (23.4%) produced carbapenemases, most of them being KPC enzymes (54.2%), followed by OXA-48-like (24.5%), NDM (20.3%), and VIM (6.5%). Three isolates (0.6%, all S. marcescens) produced SEM enzymes and one K. pneumoniae (0.2%) produced an IMP. CFDC was highly active against CP isolates, with >90% of the KPC-, OXA-48-like, VIM-, IMP-, and SEM-producing and 85.4% of NDM-producing isolates being susceptible according to FDA/CLSI breakpoints (Table 1). While susceptibilities were lower when applying EUCAST breakpoints, because of the number of isolates with CFDC MIC values of 4 µg/mL, CFDC remained one of the most active agents. Compared to β-lactam-β-lactamase inhibitor combinations, CFDC showed higher susceptibility against the CP isolates, mainly the result of the increased stability of CFDC against metallo-β-lactamases. Conclusion CFDC is active against CP Enterobacterales, regardless of the carbapenemase produced. In contrast, β-lactam-β-lactamase inhibitor combinations showed variable activity. CFDC should be considered as a treatment option when CP Enterobacterales are encountered. Disclosures Boudewijn L. DeJonge, PhD, Shionogi Inc.: Employee Sean T. Nguyen, PharmD, Shionogi Inc.: Employee Jason J. Bryowsky, PharmD, MS, Shionogi: Employee Rodrigo Mendes, PhD, Shionogi & Co., Ltd.: Grant/Research Support Christopher M. Longshaw, PhD, Shionogi BV: Employee Miki Takemura, n/a, Shionogi & Co., Ltd.: Employee Yoshinori Yamano, PhD, Shionogi & Co., Ltd.: Employee

513. Cefiderocol Retains in vitro Activity Against Enterobacterales Non-Susceptible to β-lactam-β-lactamase Inhibitor Combinations

Abstract Background Over the past ten years β-lactam-β-lactamase inhibitor combinations, such as ceftazidime-avibactam (CZA), meropenem-vaborbactam (MVB), imipenem-relebactam (I/R) have been introduced onto the market as options to treat infections caused by carbapenem-resistant Enterobacterales. With resistance emerging against these agents, we assessed the in vitro activity for cefiderocol (CFDC), a siderophore conjugated cephalosporin, against isolates that were collected between 2020-2022 in Europe and the USA as part of the SENTRY Antimicrobial Surveillance Program that were non-susceptible CZA, MVB, or I/R.Table 1.Activity for cefiderocol, ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-relebactam against various non-susceptible phenotypic subsets of Enterobacterales isolates collected from European and US hospitals as part of the SENTRY surveillance program (2020-2022). Methods A total of 24,084 Enterobacterales were collected and minimum inhibitory concentrations (MIC) for CZA, MVB, I/R were determined according to CLSI guidelines using broth microdilution with cation-adjusted Mueller-Hinton broth (CAMHB), while for CFDC iron-depleted CAMHB was used. Susceptibility was assessed according to 2024 CLSI, FDA, and EUCAST breakpoints. Non-susceptibility to CZA, MVB, I/R was assessed using CLSI breakpoints. Results Few isolates collected were non-susceptible to CZA (0.6%), MVB (0.8%), or I/R (1.0%). 83.9%, 91.4% and 92.6% of CZA-NS, MVB-NS, and I/R-NS isolates tested susceptible for CFDC, according to CLSI breakpoints (Table 1). These percentages were lower when EUCAST breakpoints were applied; 58.4%, 68.8% and 72.9%, respectively, a result of a significant number of isolates with CFDC MIC values of 4 µg/mL. Regardless of the breakpoints used, susceptibility to CFDC was higher compared to any of the β-lactam-β-lactamase inhibitor combinations, which demonstrated a high degree of cross-resistance. This high degree of cross-resistance could be largely explained by the presence of metallo-β-lactamases in CZA-NS (126/137), MVB-NS (104/186) and I/R-NS (113/229) isolates. Conclusion CFDC remains active against Enterobacterales that are non-susceptible against β-lactam-β-lactamase inhibitor combinations. In contrast, cross resistance was observed for the β-lactam-β-lactamase inhibitor combinations. CFDC should be considered as a treatment option when Enterobacterales non-susceptible to β-lactam-β-lactamase inhibitor combinations are encountered. Disclosures Boudewijn L. DeJonge, PhD, Shionogi Inc.: Employee Sean T. Nguyen, PharmD, Shionogi Inc.: Employee Jason J. Bryowsky, PharmD, MS, Shionogi: Employee Rodrigo E. Mendes, PhD, JMI: RM is an employee of JMI. JMI was contracted by and received financial support from GSK to conduct gepotidac|Paratek Pharmaceuticals: Advisor/Consultant|Paratek Pharmaceuticals: Grant/Research Support Christopher M. Longshaw, PhD, Shionogi BV: Employee Miki Takemura, n/a, Shionogi & Co., Ltd.: Employee Yoshinori Yamano, PhD, Shionogi & Co., Ltd.: Employee

P-1361. Cefiderocol Activity against Pseudomonas aeruginosa, Including Resistant Subsets and Isolates Carrying Carbapenemase β-lactamase Genes, from United States Hospitals (2020–2023)

Abstract Background Pseudomonas aeruginosa (PSA) possess various intrinsic treatment-limiting resistance mechanisms, leading to decreased antibiotic permeability, and also the ability to acquire resistance. Cefiderocol (FDC) is a siderophore cephalosporin that uses the iron transport systems of Gram-negative bacteria to optimize cell entry. The activity of FDC and comparator agents were evaluated against PSA causing infections in US hospitals, including resistant subsets, as part of the SENTRY Antimicrobial Surveillance Program. Methods 4,400 PSA were collected from 36 sites in the US in 2020–2023. Susceptibility (S) testing was performed by broth microdilution with cation-adjusted Mueller-Hinton broth (CAMHB) for comparators and iron-depleted CAMHB for FDC. CLSI/FDA criteria were applied. Isolates with imipenem (IMI) or meropenem MIC ≥4 mg/L (nonS by CLSI) were screened for β-lactamase genes. Multidrug resistance (MDR) was defined as nonS to ≥3 drug classes by CLSI; whereas, extensively drug resistance (XDR) was defined as nonS to all but 2 or fewer drug classes. Results 14.6% (643/4,400) and 4.7% (206/4,400) PSA isolates were MDR and XDR, respectively. 22.3% (980/4,400) PSA were carbapenem-nonS, with only 9 (0.9%) strains carrying carbapenemases. FDC and β-lactam/β-lactamase inhibitor (BL/BLI) combinations showed S of > 95% against all PSA, except for piperacilin-tazobactam (79.9%S) (Table). FDC (90.8–99.4%) showed MIC50 of 0.12 mg/L and MIC90 of 0.5–1 mg/L against MDR, XDR and carbapenem-nonS isolates, whereas BL/BLI showed S of 2.9–90.2%. FDC (100%S) inhibited all PSA carrying carbapenemases at the CLSI S breakpoint of ≤2 mg/L. Other comparators showed S of < 35% against the latter subset. FDC (MIC50/90, 0.12/0.5 mg/L; 96.8–99.4%S) had MIC 4- to 8-fold lower than IMI-relebactam (MIC50/90, 1/2 mg/L; 90.0%S) and cetolozane-tazobactam (MIC50/90, 1/4 mg/L; 90.9%S), which were also active against carbapenem-nonS PSA absent of carbapenemase genes. Conclusion FDC showed potent and cosistent activity against PSA clinical isolates from US hospitals, including resistant subsets and those with or without carbapenemase genes. These data demonstrate FDC activity against PSA resistant subsets, for which antibiotic treatment options are limited. Disclosures Rodrigo E. Mendes, PhD, GSK: Grant/Research Support

P-650. In vitro Activity of Cefiderocol and Comparator Agents Against Global Enterobacterales Isolates From Hospitalized Patients with Pneumonia Collected as Part of the SENTRY Surveillance Program (2020-2022)

Abstract Background The in vitro activity of cefiderocol (CFDC) and comparator agents was evaluated against Enterobacterales isolates collected from patients with pneumonia during 2020-2022 as part of the SENTRY Antimicrobial Surveillance Program. Methods 5,793 Enterobacterales (40.5% Klebsiella spp., 19.6% E. coli, 13.6% Serratia spp., 11.6% Enterobacter spp., 5.1% Proteus spp., 5% Citrobacter spp., 4.6% other) were collected from pneumonia patients and tested for susceptibility (%S) using CLSI broth microdilution with cation-adjusted Mueller-Hinton broth (CAMHB) or iron-depleted CAMHB for CFDC. Comparator agents included β-lactam/β-lactamase inhibitor (BL/BLI) combinations ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C/T), imipenem-relebactam (I-R) meropenem-vaborbactam (M-V), piperacillin-tazobactam as well as meropenem (MEM), cefepime and ceftazidime . Susceptibility was interpreted according to 2024 CLSI|FDA, and EUCAST breakpoints. Carbapenem resistant Enterobacterales (CRE) was defined as resistant to imipenem and MEM. Multidrug-resistant (MDR) Enterobacterales was defined as nonsusceptible to at least 1 drug from ≥3 classes and extensively drug resistant (XDR) as susceptible to ≤2 classes per 2024 CLSI criteria. Results 47% and 53% of isolates were from North America and Europe, respectively. CFDC, MEM, CZA, I-R and M-V all showed high susceptibility against all Enterobacterales isolates ( >94/ >97 %S using CLSI|FDA/EUCAST breakpoints). Against CRE, CFDC (99.7/83.5 %S CLSI|FDA/EUCAST) was the most active agent while CZA was the second most active (74.7%S CLSI|FDA and EUCAST). CFDC, CZA, I-R, M-V were most active against MDR isolates ( >93/ >94 %S CLSI|FDA/EUCAST) however, CFDC (94.4/81.1 %S CLSI|FDA/EUCAST) was the only agent with appreciable activity against XDR isolates. Conclusion CFDC demonstrated high in vitro activity against Enterobacterales isolated from hospitalized patients with pneumonia, including MDR and XDR isolates. Susceptibility for comparator agents, comprising BL/BLI combinations, was generally lower against isolates with CRE and XDR phenotypes. CFDC represents an important treatment option for pneumonia infections caused by Enterobacterales with presumed or defined CRE, MDR, or XDR phenotypes. Disclosures Jason J. Bryowsky, PharmD, MS, Shionogi: Employee Boudewijn L. DeJonge, PhD, Shionogi Inc.: Employee Sean T. Nguyen, PharmD, Shionogi Inc.: Employee Rodrigo E. Mendes, PhD, GSK: Grant/Research Support Christopher M. Longshaw, PhD, Shionogi BV: Employee Miki Takemura, n/a, Shionogi & Co., Ltd.: Employee Yoshinori Yamano, PhD, Shionogi & Co., Ltd.: Employee

The hidden threat: Klebsiella pneumoniae may develop co-resistance to colistin and cefiderocol under pressure of colistin.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) has become a global concern owing to its difficult treatment. This study aimed to determine the impact of colistin resistance on susceptibility to cefiderocol. The colistin-susceptible clinical strain CRKP12-130 (colistin minimum inhibitory concentration [MIC] 0.5 mg/L) was cultured in medium containing 4× and 8× the MIC of colistin. Eight colistin-resistant derivatives were randomly selected for susceptibility testing of cefiderocol and zeta potential changes. To compare the impact of colistin resistance on bacterial uptake of iron, growth curve experiments were conducted in cation-adjusted Mueller-Hinton broth (CAMHB) and iron-depleted CAMHB (ID-CAMHB). Resistant strains and the original strain CRKP12-130 were subjected to next-generation sequencing. Colistin MICs ranged from 16 to 128 mg/L for the eight colistin-resistant derivatives. The key genetic variants identified in colistin-resistant strains involved insertions and deletions in mgrB, and missense mutations in pmrB and phoQ. The colistin-resistant derivatives also exhibited reduced susceptibility to cefiderocol, with MICs increasing from 1 mg/L to 2-8 mg/L. Additionally, colistin-resistant strains demonstrated higher zeta potentials, ranging from -45.2 mV to levels between -32.8 mV and -14.2 mV. Resistant strains showed a more significant decrease in growth rate when cultivated in ID-CAMHB medium. This study investigated the phenomenon of co-resistance to colistin and cefiderocol in CRKP under pressure of colistin. The simultaneous decrease in susceptibility poses a potential threat to the efficacy of clinical treatment of CRKP infections.

A multicenter performance evaluation of cefiderocol MIC results: ComASP in comparison to CLSI broth microdilution.

There are very limited commercial methods available to clinical laboratories for cefiderocol minimum inhibitory concentration (MIC) testing. The Compact Antimicrobial Susceptibility Panel (ComASP) Cefiderocol method includes iron-depleted cation-adjusted Mueller-Hinton broth, which eliminates variability in cefiderocol MIC results based on iron levels. The lyophilized multi-well format of ComASP also provides for room temperature storage. In comparison to what an individual lab may do for method verification, this multi-site, multi-isolate study provides a robust evaluation and greater assurance to clinical microbiologists of the method's accurate and reproducible performance.

Real-world performance of susceptibility testing for cefiderocol: insights from a prospective multicentre study on Gram-negative bacteria.

Cefiderocol is a novel siderophore-conjugated cephalosporin developed for the treatment of multidrug-resistant Gram-negative bacterial (GNB) infections. However, the current gold standard for cefiderocol susceptibility testing, broth microdilution (BMD) using iron-depleted cation-adjusted Mueller-Hinton broth, presents challenges for many microbiology laboratories. In this study, we evaluate the real-world performance of disc diffusion (DD) and a commercial BMD method (ComASP®) to test cefiderocol susceptibility in a series of isolates collected prospectively from severely ill patients in a multicentre study. The susceptibilities of 1472 isolates (632 Enterobacterales, 532 Pseudomonas aeruginosa, 84 Acinetobacter spp. and 224 Stenotrophomonas maltophilia) collected in 60 Spanish hospitals were analysed following the EUCAST 2023 and 2024 criteria. We assessed the performance of DD (cefiderocol 30 μg disc, Liofilchem) and a commercial BMD method (ComASP® Cefiderocol, Liofilchem). A total of 1408 and 1450 isolates were susceptible by DD and ComASP® BMD, respectively. Overall, the agreement between both methods was 96.9%. Forty-four isolates were resistant by DD but susceptible by ComASP® BMD, and two were susceptible by DD but resistant by ComASP® BMD (Acinetobacter baumannii isolates). Adoption of the updated 2024 EUCAST DD breakpoints and areas of technical uncertainty (ATUs) led to a decrease in susceptibility among Enterobacterales (95.3% versus 92.6%). DD is a straightforward, rapid and accessible method for routine determination of cefiderocol susceptibility in real-world practice. ComASP® BMD shows a high agreement with DD in susceptible isolates and may help to resolve DD interpretability concerns in isolates with susceptibility results within the ATU, but caution is warranted when testing resistant isolates.

Surveillance of In Vitro Activity of Cefiderocol Against Carbapenem-Resistant Gram-Negative Clinical Isolates in a Tertiary Care Hospital.

Antibiotic resistance among Gram-negative bacterial isolates is increasingly observed. With the emergence of carbapenem-resistant and pan-resistant pathogens, treating these resistant infections is becoming more challenging due to the limited number of effective drugs. There is a desperate need for the discovery of new antibiotics with novel mechanisms of action. Cefiderocol is one such novel antibiotic with a unique siderophore-based mechanism of action, which has been recently approved for clinical use against drug-resistant pathogens. The present study aims to identify the in vitro activity of cefiderocol against major carbapenem-resistant clinical isolates, including those resistant to colistin. One hundred and one carbapenem-resistant clinical isolates were included in the study. Identification and antibiotic susceptibility testing were performed using the automated VITEK® 2 Compact (bioMérieux SA, Marcy-l'Étoile, France) identification and susceptibility testing system, except for colistin and cefiderocol. Colistin resistance in Enterobacterales and Pseudomonas aeruginosa was assessed using the agar dilution minimum inhibitory concentration method, while for Acinetobacter baumannii, broth microdilution method was employed. Cefiderocol susceptibility testing was conducted using the Kirby-Bauer disc diffusion method with 30 µg discs on standard Mueller-Hinton agar plates. For selected isolates, cefiderocol minimum inhibitory concentration detection was performed using broth microdilution with iron-depleted cation-adjusted Mueller-Hinton broth. Of the total 101 isolates, the majority (75, 74.25%) were Enterobacterales which includedKlebsiella pneumonia (42, 41.58%) and Escherichia coli (33, 32.67%), followed by Pseudomonas aeruginosa (13, 12.87%) and Acinetobacter baumannii (10, 9.9%). Only three (2.97%)of the isolates were Stenotrophomonas maltophilia. Most of the isolates were susceptible to cefiderocol, with only four (3.96%) isolates showing resistance. Colistin resistance was observed in six (6.12%) of the isolates. There was a good correlation between disc diffusion testing and broth microdilution testing for the detection of cefiderocol-resistant isolates. No cross-resistance with colistin was observed, as all colistin-resistant isolates were uniformly susceptible to cefiderocol Conclusion: Cefiderocol is highly effective with good in vitro activity against the majority of carbapenem-resistant pathogens. While some isolates do show resistance, it is relatively uncommon. Given its safety profile compared to colistin, cefiderocol can serve as an alternative to colistin to treat carbapenem-resistant infections and it may be considered even for the management of colistin-resistant cases. Disc diffusion testing is a reliable method for identifying cefiderocol-resistant isolates in routine clinical and diagnostic laboratories, especially in resource-limited settings.

2790. Activity of Cefiderocol and Comparator Agents Against Pediatric Isolates of Enterobacterales, Pseudomonas aeruginosa, Acinetobacter baumannii-calcoaceticus species complex, and Stenotrophomonas maltophilia from the SENTRY Surveillance Program (2020-2022)

Abstract Background Cefiderocol (CFDC) is a siderophore cephalosporin with broad activity against Gram-negative bacteria including multi-drug resistant isolates. The in vitro activity of CFDC and comparator agents was evaluated against pediatric (0-17 years old) isolates collected in 2020–2022 as part of the SENTRY Antimicrobial Surveillance Program. In vitro Activity of Cefiderocol and Comparator Agents Against Pediatric Isolates Methods 2,249 Enterobacterales (ENT), 707 P. aeruginosa, 194 Acinetobacter baumannii-calcoaceticus complex (ABC) and 220 S. maltophilia from the USA and Europe were tested for susceptibility (%S) by broth microdilution with cation-adjusted Mueller-Hinton broth (CAMHB). Iron-depleted CAMHB was applied for CFDC. Comparators included newer β-lactam/β-lactamase inhibitor (BL/BLI) combinations ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C/T), imipenem-relebactam (I-R) and meropenem-vaborbactam (MVB) as well as ampicillin/sulbactam (SAM) meropenem (MEM) and colistin (CST). %S was interpreted according to 2023 CLSI & EUCAST breakpoints. Carbapenem non-susceptible (CarbNS) was defined as non-susceptibility to imipenem and MEM. Results All agents displayed >96 %S for ENT while CFDC (MIC50/90, 2/4 mg/L; 91.7 %S) was the most active agent against CarbNS ENT. P. aeruginosa susceptibilities to CFDC and BL/BLI combinations were >97.0%. CFDC was the most potent agent against CarbNS P. aeruginosa with MIC50/90 values of 0.12/0.25 mg/L and 100 %S & 98.5 %S per CLSI & EUCAST breakpoints, respectively. ABC susceptibility to CFDC was >97% per CLSI & EUCAST while the susceptibility for MEM was 87.1% (CLSI & EUCAST) and SAM was 80.9% (CLSI). CFDC (MIC50/90, 0.25/1 mg/L; 95.7 %S) displayed better in vitro potency in CarbNS ABC as compared to SAM (MIC50/90, 32/ >64 mg/L; 17.4 %S CLSI) and CST (MIC50/90, 0.5/ >8 mg/L; 78.3%S EUCAST). Among pediatric S. maltophilia, CFDC was the most active agent with MIC50/90, 0.06/0.25 and 100 %S per CLSI & EUCAST breakpoints. Conclusion CFDC was a highly active β-lactam against contemporary pediatric isolates of Enterobacterales, P. aeruginosa, ABC, and S. maltophilia, including CarbNS subsets for which treatment options are limited. These data suggest CFDC may be a valuable treatment for serious Gram-negative infections in pediatric patients. Disclosures Sean T. Nguyen, PharmD, Shionogi: Employee|Shionogi, Inc: Employee Boudewijn L. DeJonge, PhD, Shionogi Inc.: Employee Jason J. Bryowsky, PharmD, MS, Shionogi Inc.: Employee Anne Henriksen, PhD, Shionogi: Employee Christopher M. Longshaw, PhD, Shionogi BV: Employee Joshua Maher, PhD, AbbVie: Grant/Research Support|Affinity Biosensors: Grant/Research Support|AimMax Therapeutics, Inc: Grant/Research Support|Alterity Therapeutics: Grant/Research Support|Amicrobe, Inc: Grant/Research Support|Arietis Pharma: Grant/Research Support|Armata Pharmaceuticals, Inc: Grant/Research Support|Astrellas Pharma, Inc.: Grant/Research Support|Basilea Pharmaceutica AG: Grant/Research Support|Becton Dickinson And Company: Grant/Research Support|bioMerieux, Inc: Grant/Research Support|Boost Biomes: Grant/Research Support|Diamond V: Grant/Research Support|Fedora Pharmaceuticals, Inc: Grant/Research Support|Iterum Therapeutics plc: Grant/Research Support|Johnson & Johnson: Grant/Research Support|Kaleido Biosciences, Inc.: Grant/Research Support|Meiji Seika Pharma Co. Ltd.: Grant/Research Support|National Institutes of Health: Grant/Research Support|Pfizer Inc.: Grant/Research Support|Roche Holding AG: Grant/Research Support|Shionogi Inc.: Grant/Research Support|Summmit Therapeutics, Inc.: Grant/Research Support|Zoetis Inc: Grant/Research Support Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Entasis: Grant/Research Support|GSK: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Miki Takemura, n/a, Shionogi & Co., Ltd.: Stocks/Bonds Yoshinori Yamano, PhD, Shionogi HQ: Employee

2761. Activity of Cefiderocol and Comparator Agents Against Achromobacter and Burkholderia Isolates, Collected During 2020-2022 as Part of SENTRY Antimicrobial Surveillance Program

Abstract Background Achromobacter and Burkholderia species are opportunistic pathogens in individuals with an immunodeficiency, most notably cystic fibrosis. Cefiderocol (CFDC) is a siderophore-conjugated cephalosporin with broad activity against Gram-negative bacteria. In this study, the activity of CFDC and comparator agents was determined against isolates of Achromobacter and Burkholderia cepacia species complex, collected in 2020–2022 in Europe and the USA as part of the SENTRY antimicrobial surveillance program. Activity of cefiderocol and comparator agents against Achromobacter and Burkholderia Isolates Methods Minimum inhibitory concentrations (MICs) were determined according to CLSI guidelines against 167 Achromobacter and 160 Burkholderia cepacia species complex isolates, using broth microdilution with cation-adjusted Mueller-Hinton broth (CAMHB) for comparator agents and iron-depleted CAMHB for CFDC. Comparator agents included β-lactam/β-lactamase inhibitor combinations ceftazidime-avibactam, ceftolozane-tazobactam, imipenem-relebactam, meropenem-vaborbactam, piperacillin-tazobactam, as well as meropenem, ceftazidime, levofloxacin, amikacin, trimethoprim-sulfamethoxazole, and minocycline. Susceptibility was assessed for agents with CLSI breakpoints. For agents without established CLSI breakpoints, only MIC50, MIC90 and MIC ranges were reported. Results CFDC was the most potent agent tested against Achromobacter, showing MIC50 and MIC90 values of 0.03 and 0.25 µg/mL and all isolates were inhibited at ≤4 µg/mL (Table). Isolates from cystic fibrosis patients (n=15) showed higher MIC50 and MIC90 values for most agents, but CFDC MIC50 and MIC90 values remained low (0.06 and 0.25 µg/mL, respectively). Against Burkholderia cepacia species complex, CFDC was the most potent agent tested, with MIC50 and MIC90 values of 0.06 and 0.5 µg/mL, and 156 out of 160 isolates inhibited at ≤4 µg/mL. None of the comparator agents showed >90% susceptibility against these isolates (Table). Conclusion CFDC showed potent activity against a set of contemporary clinical Achromobacter and Burkholderia cepacia species complex isolates. These in vitro data suggest that CFDC could be an important treatment option for infections caused by these opportunistic pathogens. Disclosures Boudewijn L. DeJonge, PhD, Shionogi Inc.: Employee Sean T. Nguyen, PharmD, Shionogi: Employee|Shionogi, Inc: Employee Jason J. Bryowsky, PharmD, MS, Shionogi Inc.: Employee Christopher M. Longshaw, PhD, Shionogi BV: Employee Joshua Maher, PhD, AbbVie: Grant/Research Support|Affinity Biosensors: Grant/Research Support|AimMax Therapeutics, Inc: Grant/Research Support|Alterity Therapeutics: Grant/Research Support|Amicrobe, Inc: Grant/Research Support|Arietis Pharma: Grant/Research Support|Armata Pharmaceuticals, Inc: Grant/Research Support|Astrellas Pharma, Inc.: Grant/Research Support|Basilea Pharmaceutica AG: Grant/Research Support|Becton Dickinson And Company: Grant/Research Support|bioMerieux, Inc: Grant/Research Support|Boost Biomes: Grant/Research Support|Diamond V: Grant/Research Support|Fedora Pharmaceuticals, Inc: Grant/Research Support|Iterum Therapeutics plc: Grant/Research Support|Johnson & Johnson: Grant/Research Support|Kaleido Biosciences, Inc.: Grant/Research Support|Meiji Seika Pharma Co. Ltd.: Grant/Research Support|National Institutes of Health: Grant/Research Support|Pfizer Inc.: Grant/Research Support|Roche Holding AG: Grant/Research Support|Shionogi Inc.: Grant/Research Support|Summmit Therapeutics, Inc.: Grant/Research Support|Zoetis Inc: Grant/Research Support Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Entasis: Grant/Research Support|GSK: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Miki Takemura, n/a, Shionogi & Co., Ltd.: Stocks/Bonds Yoshinori Yamano, PhD, Shionogi HQ: Employee

Assessment of cefiderocol disk diffusion versus broth microdilution results when tested against Acinetobacter baumannii complex clinical isolates.

The aim of this study was to evaluate the correlation between inhibitory zones and minimum inhibitory concentrations (MICs) when testing cefiderocol against Acinetobacter baumannii complex using disk diffusion and the broth microdilution (BMD) method according to the Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria. Four-hundred and sixty-eight non-duplicated A. baumannii complex clinical isolates were collected from 56 hospitals of the China Antimicrobial Surveillance Network from 2019 to 2021. BMD using iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) and standard disk diffusion methods were performed according to CLSI guidelines. Results were interpreted according to the CLSI and EUCAST breakpoints. Categorical agreement (CA), minor error (mE), major error (ME), and very major error (VME) were calculated for disk diffusion methods. The susceptibilities of all A. baumannii complex isolates by BMD were 98.7% (CLSI) and 97.6% (EUCAST). For all A. baumannii complex isolates, CA was 98.1% (CLSI) and 97.0% (EUCAST), with 0.9% (CLSI) and 1.9% (EUCAST) of VME, respectively. For the carbapenem-susceptible A. baumannii complex, the CA was 100%, with no mE or VME using both CLSI and EUCAST breakpoints. For carbapenem-resistant A. baumannii complex, CA was 97.5% (CLSI) and 96.2% (EUCAST), with 1.1% (CLSI) and 2.5% (EUCAST) of VME, respectively. Regarding the difficult-to-treat resistance A. baumannii complex isolates, CA was 97.6% (CLSI) and 95.7% (EUCAST), with 1.2% (CLSI) and 3.1% (EUCAST) of VME, respectively. Cefiderocol disk diffusion was difficult to assess in this study. Very few isolates were resistant to cefiderocol by BMD using CLSI breakpoint, and these were categorized as susceptible with the disk diffusion test. This study did, however, show that the main proportion of A. baumannii isolates were susceptible to cefiderocol by BMD, including carbapenem-resistant A. baumannii. IMPORTANCE Carbapenem-resistant Acinetobacter baumannii is a major global health concern due to its high prevalence and limited treatment options. Cefiderocol is the only novel Food and Drug Administration (FDA)-approved β-lactam agent for the salvage treatment of carbapenem-resistant A. baumannii infection. Currently, a commercial automated susceptibility testing panel of cefiderocol is unavailable. Both the preparation of iron-depleted cation-adjusted Mueller-Hinton broth and the performance of broth microdilution are cumbersome in routine microbiology laboratories. A disk diffusion method is convenient for cefiderocol antimicrobial susceptibility testing, but limited data are available specifically for A. baumannii clinical isolates. Moreover, the Clinical and Laboratory Standards Institute published revisions to the A. baumannii cefiderocol disk diffusion breakpoints in 2022. Hence, we evaluated the performance of cefiderocol disk diffusion compared with the reference BMD against A. baumannii clinical isolates, especially those with cefiderocol zone diameters ≤ 14 mm.