Non Susceptibility Research Articles

313. Genomic Features Associated with Non-susceptibility to Cefiderocol in Pseudomonas aeruginosa and Cross-resistance to Novel β-lactam/β-lactamase Inhibitors in the Prospective Observational Pseudomonas (POP) study

Abstract Background Cefiderocol (FDC) is a last-line agent used to treat carbapenem-resistant P. aeruginosa (CR-PA). We evaluated the prevalence of FDC heteroresistance (hR) and non-susceptibility (NS) in the POP cohort and associations with genes previously related to FDC resistance.Figure 1.Proportion of isolates harboring genomic feature by geographic region (US vs non-US). Methods 972 genomes from the multicenter, global POP study were screened for mutations in genes implicated in decreased FDC susceptibility: ampC, pirR, pirS, pirA, piuA/D, ftsI, cpxS and exogenous β-lactamases. A representative population was selected to encompass all variants as well as controls obtained by phylogenetically mapping each mutant isolate with a closest non-mutant isolate (n=187). All strains were assessed by broth microdilution (BMD) and population analysis profile (PAP). FDC NS was defined as minimum inhibitory concentration (MIC) ≥ 8 μg/m. hR was determined by PAP area under the curve > 80, per the 99% confidence interval for PAO1. Chi-squared test was used to assess correlation of ceftolozane-tazobactam (C/T), ceftazidime-avibactam (CZA), and imipenem-relebactam (IMR) categorization and FDC hR/NS as well as gene correlations with FDC hR/NS and geographic region of the isolate. Association between FDC phenotype and MIC category of novel β-lactam/β-lactamase inhibitor combinations. Results Over 20% of isolates displayed a NS or hR FDC phenotype (n=39: 28 hR, 11 MIC ≥ 8 μg/mL), equally distributed among US and non-US isolates (Fig 1, P =0.36). Isolates with increased C/T, CZA, and IMR MICs were more likely to be FDC NS or hR (Tbl 1). IMR susceptibility was low across FDC NS, hR and susceptible cohorts. The combination of mutations in both ampC and the PirRS system demonstrated higher risk for FDC NS or hR (Tbl 2, P = 0.0003), but isolated mutations in either ampC or PirRS did not increase risk for FDC NS or hR. VEB and NDM β-lactamases were present in non-US isolates and their presence correlated with FDC NS or hR (Tbl 2, P = 0.0003, 0.0017). Mutations in the PirRS system showed a geographic predisposition in US isolates (Fig 1, P= 0.0047), while exogenous β-lactamases were associated with international isolates (P < 0.0001). Genotypic determinants associated with FDC susceptibility phenotype. Conclusion NS and hR to FDC is prevalent globally among CR-PA and is associated with reduced C/T, CZA, and IMR susceptibility. NS and hR isolates were associated with mutations in ampC, pirRS, and the exogenous β-lactamases VEB, NDM. Further studies are needed to define clinical significance of FDC hR. Disclosures Cesar A. Arias, MD, MSc, PhD, UpToDate, Inc.: Royalties Vincent Tam, Pharm. D., AbbVie Inc: Advisor/Consultant Michael J. Satlin, MD, AbbVie: DSMB participant|bioMerieux: Grant/Research Support|Merck: Grant/Research Support|Selux Diagnostics: Grant/Research Support|SNIPRBiome: Grant/Research Support William R. Miller, M.D., Merck: Grant/Research Support|UptoDate: Royalties

P-1851. Influence of the COVID-19 Pandemic on Antimicrobial Resistance Patterns in Pediatric Group A Streptococcus Infections in Houston, TX

Abstract Background Group A Streptococcus (GAS) causes a large spectrum of disease, including invasive, pharyngeal and skin / soft tissue (SSTI)1. Penicillin remains the mainstay therapy but recently, resistance to second-line therapies has steadily increased, especially after COVID19, with macrolide-resistant GAS as an emerging threat2. Given recent surges of GAS associated with later stages of the pandemic,4 we sought to compare pre-pandemic (2013-2019) and pandemic (2020-2023) GAS epidemiology and antimicrobial resistance patterns.Figure 1Total number of isolates and distribution of disease types per year. Methods GAS isolates were collected from Texas Children’s Hospital laboratory from January 2013-December 2023 and grouped into pre-pandemic and pandemic periods. Disease type [invasive (INV), skin and soft tissue infection (SSTI), or pharyngeal (PHG)] was determined from the medical record. Isolates were grown, stocked and emm typed5. Resistance to tetracycline, erythromycin, and clindamycin was determined by disk diffusion. Intermediate and resistant strains were collectively considered non-susceptible (NS).Figure 2Frequency of antibiotic non-susceptibility by year Results We analyzed 2,717 isolates (pre-pandemic n=1640; pandemic n=1077) and observed a similar distribution of disease types between the two periods (Figure 1). Distribution of emm types differed with emm12 (1.7-fold) and emm3 (1.6-fold) increasing significantly and emm89 (0.6-fold), emm4 (0.6-fold), emm87 (0.4-fold) and emm6 (0.3-fold) decreasing significantly. Overall NS to any antibiotic increased from 19% to 39% between the two periods (P< 0.0001). NS in the pandemic period was primarily driven by NS to clindamycin, increasing by >3-fold (6% vs 20%) (Figure 2). Among emm types showing NS to clindamycin pre vs pandemic, emm28 increased 10-fold (3% vs 31%, P< 0.0001), emm1 increased 5-fold (5% vs 24%, P =< 0.001), and emm12 increased 2.6-fold (6% vs 16%, P< 0.001) (Figure 3). NS to any antibiotic increased independent of disease type between the two periods. Figure 3 Frequency of clindamycin non-susceptibility by emm type Conclusion NS increased significantly in pandemic period, mostly driven by NS to clindamycin. A small subset of emm types disproportionately contributed to clindamycin NS in pandemic period, although the mechanism remains unknown. Clinicians should be aware of the possible reduced effectiveness of clindamycin in pediatric GAS infections. Disclosures Jonathon C. McNeil, MD, Nabriva: site investigator on clinical trial Anthony R. Flores, MD, MPH, PhD, GlycosBio, Inc: Grant/Research Support

P-1476. Cefiderocol Treatment Outcomes and Risk Factors for Gram-negative Bacterial Infection Treatment Failure

Abstract Background The IDSA 2023 guidance lacks strong evidence about cefiderocol (FDC) efficacy and real-world data are limited. The aim of this study was to evaluate effectiveness, safety, and risk factors for clinical failure (ClinF) associated with FDC use in hospitalized patients. Methods This was a retrospective, observational study. Adults treated with an initial course of FDC for ≥ 48 hours from Feb 2020 - Aug 2023 were included. Primary outcome was clinical success (ClinS) defined as a composite of survival, resolution of signs and symptoms, and absence of both recurrent infection or microbiological failure. Factors associated with success and failure were compared on univariable analysis and those with a p-value < 0.2 and FDC monotherapy were considered for inclusion in a multivariable model for ClinF. Results 87 patients were included. Most common pathogens: Pseudomonas spp (49%), Acinetobacter spp (29%), and Klebsiella spp 16%. Carbapenem-resistance was reported for 93% of isolates and majority of cases were from a respiratory source (72%). At FDC initiation, 39 patients (45%) were admitted to the ICU and the median PITT bacteremia score was 3 (IQR, 1.5-4). ClinS was achieved in 32 patients (37%). Within this composite, 70% survived, 59% resolved their signs/symptoms, 62% had absence of microbiologic failure, and 63% did not recur within 30 days. 16 patients (18%) developed FDC non-susceptibility (NS) within 90 days. ClinS was associated with urine and intra-abdominal sources, while ClinF was associated with COPD, mechanical ventilation, respiratory sources, and higher PITT bacteremia scores. No significant differences found between age, Charlson comorbidity index score, or monotherapy and combination therapy. COPD was found to be an independent factor associated with ClinF [OR 11.5 (95% CI 1.63-82.28, p=0.014)]. Comparing patients who developed FDC NS to those that did not, solid organ transplant [7(44) vs 14(20); p=0.088], longer antibiotic days prior to FDC [14.5 d vs 7 d; p=0.079], and longer FDC duration [14 d vs 10 d; p=0.023] were more common in those that developed NS. Conclusion In this single center experience with mostly respiratory infections, FDC was successfully used with ClinF being associated with underlying illness. The potential development of NS should be further explored. Disclosures All Authors: No reported disclosures

P-1835. Evolution of Antibiotic Resistance Patterns in Acinetobacter baumannii Clinical Isolates in Response to Bleach Exposure

Abstract Background Acinetobacter baumannii (Ab) is a common cause of drug-resistant infections. Ab rapidly acquires antibiotic resistance and can survive exposure to numerous antiseptics such as bleach. Prior research has demonstrated increased antibiotic resistance in Ab following exposure to antiseptics, likely due to increased expression of efflux pumps, but the relationship between antiseptic resistance and antibiotic resistance is not well known. In this study, we describe the evolution of antibiotic resistance in two Ab isolates following exposure to bleach.Table 1:Antibiotic Susceptibilities for Evolved Strains of ACB3 Antibiotic susceptibilities for the evolved strains of ACB3 are depicted. For each strain, antibiotic susceptibilities were determined based on Clinical & Laboratory Standards Institute (CLSI) reference standards, and were classified as susceptible (S) or non-susceptible (NS). Non-susceptible values were those that were determined to be either intermediate or resistant. ACB3 was initially susceptible to most antibiotics at G0, and developed increased resistance to all antibiotic classes by G450. Methods Two Ab clinical isolates, ACB3 and ACB9, were exposed to sublethal (0.01%) concentrations of bleach and grown in triplicate, with strains selected at baseline (G0), the 450th generation (G450), and the 1000th generation (G1000) for further analysis. Antibiotic susceptibility profiles for each strain were established by determining minimum inhibitory concentration (MIC) values against 24 standard-of-care antibiotics using broth microdilution assays. Whole genome sequencing (WGS) of each strain was performed to evaluate for the emergence of new alleles to affecting antibiotic resistance.Table 2:Antibiotic Susceptibilities for Evolved Strains of ACB9 Antibiotic susceptibilities for the evolved strains of ACB9 are depicted. For each strain, antibiotic susceptibilities were determined based on Clinical & Laboratory Standards Institute (CLSI) reference standards, and were classified as susceptible (S) or non-susceptible (NS). Non-susceptible values were those that were determined to be either intermediate or resistant. NS* denotes strains with MIC values that were decreased, but not enough to be classified as susceptible. ACB9 was initially PDR at G0 but developed increased susceptibility to all aminoglycoside and tetracycline drugs by G1000. Results The ACB3 line was susceptible to most antibiotics at G0, but developed increased resistance to various antibiotics by G450, particularly against aminoglycoside and beta-lactam drugs (Table 1). Conversely, the ACB9 line was pan-drug resistant (PDR) at G0 but developed increased susceptibility to all aminoglycoside and tetracycline drugs by G1000 (Tables 2, 3). WGS of ACB9 G1000 demonstrated mutations in uvrA and uvrB, which encode nucleotide excision repair proteins, with concomitant mutations in the ABC transporter TssG, and type IV secretion system (T4SS) proteins TssC and VgrG. Mutations were observed in numerous other unidentified genes with close homology to ABC transporters, MFS efflux pumps, and OprD porins.Table 3:Minimum Inhibitor Concentration (MIC) Values for Aminoglycoside and Tetracycline Drugs Against Evolved Strains of ACB9 MIC values for aminoglycoside and tetracycline drugs against evolved strains of ACB9 are depicted. All three triplicates of ACB9 were initially resistant to all aminoglycoside and tetracycline drugs tested at G0. By G1000, all three triplicates demonstrated increased susceptibility to all aminoglycoside and tetracycline drugs, as indicated by decreased MIC values. Conclusion We describe the evolution of antibiotic resistance in Ab after exposure to bleach. ACB3 was initially susceptible to most antibiotics but developed increased resistance. ACB9 was initially PDR but developed increased susceptibility to aminoglycoside and tetracycline drugs, likely due to mutations in hypermutators uvrA and uvrB, enabling mutations in genes which may confer resistance to these drugs. Disclosures All Authors: No reported disclosures

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-1528. In Vitro Activity of Omadacycline and Comparator Agents against a Collection of Neisseria Gonorrhoeae Urine Isolates Collected from the United States During 2018-2020

Abstract Background Omadacycline (OMC) is a third-generation tetracycline (TET) class antibacterial approved for treatment of adults with acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia caused by indicated organisms. OMC is active against bacterial isolates expressing common TET resistance mechanisms and strains resistant (R) to other drug classes. In this study, the in vitro activity of OMC and comparator agents was evaluated against a contemporary collection of N. gonorrhoeae clinical isolates. In addition, analysis of publicly available genomic sequences for these isolates was performed to determine the molecular mechanisms of TET resistance. Antimicrobial activity of omadacycline and comparators tested against 100 Neisseria gonorrhoeae isolates Methods The modal minimal inhibitory concentration (MIC) of OMC and comparator agents was determined by testing in triplicate by agar dilution for 100 N. gonorrhoeae clinical isolates (BEI Resources) collected from the urethra of patients with urethritis within the US (2018-2020). R or non-susceptible (NS) phenotypes were interpreted using breakpoints published by Clinical and Laboratory Standards Institute. Resistance genes were identified from genome sequences using ResFinder 4.0. Cumulative distribution of omadacycline MIC values tested against comparator-resistant or non-susceptible N. gonorrhoeae subsets Results OMC displayed activity against N. gonorrhoeae isolates (MIC50/90, 2/4 µg/mL) that had limited susceptibility (S) to TET (13%), ciprofloxacin (CIP) (60%) and penicillin (PEN) (4%) but high S to azithromycin (AZM), cefixime (CFX), and ceftriaxone (CFN) (Table 1). Among isolates with NS or R phenotypes for comparators, the OMC MIC50/90 (when calculated) were generally not impacted, although some of these subsets had very low numbers (Table 2). The rpsJ mutation was widespread among TET-R isolates, including those with additional mutations in porB, the mtrR promoter and tet(M) (Table 3). The highest OMC MIC (8 µg/mL) correlated with combined mutations in porB and rpsJ. OMC had MICs < 1 µg/mL among isolates (n=3) with high level TET-R (MIC> 16 µg/mL), including those with tet(M). Tetracycline resistance mechanisms among tetracycline resistant Neisseria gonorrhoeae isolates Conclusion OMC MICs were 0.12-8 µg/mL against this set of N. gonorrhoeae clinical isolates and the MIC distribution was minimally impacted by isolates NS/R to AZM, CFX, CFN, CIP, PEN, or TET. These results support the further research of OMC for N. gonorrhoeae infections, especially for those with high level TET-R. Disclosures J.V. Pierce, PhD, Paratek Pharmaceuticals: Employee Alisa W. Serio, PhD, Paratek Pharmaceuticals: Employee

P-186. Trends in Antimicrobial Resistance Among Adults Across 6 Hospitals in Argentina, Brazil, and Chile, 2018-2022

Abstract Background In 2019, an estimated 1.27 million deaths were attributed to bacterial antimicrobial resistance (AR) globally. During the Coronavirus Disease 2019 (COVID-19) Pandemic, additional strain was placed on healthcare systems that may have led to further increases in AR. We evaluated AR prevalence before and after the onset of COVID-19 in 6 healthcare facilities (HCF) in South America. Methods We conducted an ecological evaluation of HCF-wide AR prevalence in 4 private and 2 public HCFs in Argentina, Brazil, and Chile; 2 HCFs per country. We calculated percentage of non-susceptible (NS) or resistant (R) to select antibiotics among clinical isolates of Acinetobacter baumannii, Pseudomonas aeruginosa, Enterococcus spp., and Enterobacterales cultured from adult acute care inpatients. We compared percentage-NS or -R between the periods pre- (March 2018–February 2020) and post- (March 2020–February 2022) onset of the COVID-19 pandemic. Chi-square or Fisher’s exact tests were used with statistical significance set at a two-tailed p< 0.05. Results When comparing 2020-2022 to 2018-2020, 2/6 hospitals showed statistically significant increases (+14.1–19.2%) in carbapenem-NS A. baumannii. For carbapenem-NS P. aeruginosa, 1/6 hospitals showed a significant increase (+76.6%) and 1/6 showed a significant decrease (-52.4%). For carbapenem-NS Enterobacterales, 2/6 hospitals had significant increases (+50.7–236.2%) and 1 exhibited a significant decrease (-91.7%). For vancomycin-R Enterococcus spp., 2/6 hospitals had significant increases (+43.9–400.0%) and 2/6 hospitals had significant decreases (-49.0-60.7%). For Enterobacterales-R to 3rd generation cephalosporins, 2/6 hospitals showed significant increases (+16.0–110.9%) and 1/6 hospitals had a significant decrease (-40.4%) (Table). Conclusion Among the isolates from our study hospitals, we noted not only significant increases but also significant decreases across multiple AR profiles associated with multi-drug resistance. These data suggest that the pandemic may have led to changes in resistance among both gram-negative and gram-positive bacteria. Given the variability in these changes, further evaluation of infection rates would be valuable to confirm these findings. Disclosures José M Munita, MD, MSD: Grant/Research Support|Pfizer: Grant/Research Support

P-1515. Outcomes of Patients with Piperacillin/Tazobactam-Non-Susceptible and Ceftriaxone-Susceptible Enterobacterales Bacteremia

Abstract Background Piperacillin/tazobactam (TZP)-non-susceptible (NS) but third-generation cephalosporin (3GC)-susceptible (S) Escherichia coli and Klebsiella pneumoniae are increasingly reported in the clinical setting. This phenotype is associated with hyperproduction of β-lactamases, including TEM-1 and SHV-1. Tailoring therapy to a 3GC in these cases may decrease carbapenem use and promote antimicrobial stewardship. However, the optimal definitive β-lactam regimen for this phenotype is unknown. This retrospective case series describes the clinical outcomes and antibiotic prescribing in patients with TZP-NS and ceftriaxone (CRO)-S Enterobacterales bacteremia at a three hospital health system. Methods We identified patients >18 years of age hospitalized with TZP-NS and CRO-S E. coli, K. pneumoniae, Klebsiella oxytoca, and Proteus mirabilis bacteremia between February 2020 and March 2024. TZP-NS and CRO-S were defined per the 2024 Clinical and Laboratory Standards Institute (CLSI) susceptibility breakpoints: TZP-S if minimum inhibitory concentration (MIC) ≤ 8/4 mg/L, TZP-NS if MIC ≥ 16/4 mg/L; CRO-S if MIC ≤ 1 mg/L, CRO-NS if MIC ≥ 2 mg/L. We included only the first isolate per patient over the study period. Antibiotic data were collected for each patient during hospitalization. We defined empiric antibiotics as the agents with the longest duration of therapy (DOT) prior to susceptibilities. Composite clinical outcomes were 30-day all-cause mortality, or 30-day readmission/emergency department (ED) visit. Results Thirty-nine patients were included in the study (Table 1). The median number of different antibiotics patients received was 3 (interquartile range [IQR] 2-3), and the median total antibiotic DOT was 14 days (IQR 9.5-17.5 days) (Table 2). Thirteen patients experienced a clinical outcome (33.3%) (Table 3). Of the patients who experienced a clinical outcome, 46.2% (6/13) received ceftriaxone during tailored therapy (median 4.5 days, IQR 3.3-7.3 days). Conclusion In this case series, most patients received TZP empirically but were tailored to CRO upon culture susceptibility availability. Larger studies are necessary to elucidate if ceftriaxone is appropriate for definitive treatment of TZP-NS and CRO-S E. coli, K. pneumoniae, K. oxytoca, and P. mirabilis bacteremia. Disclosures All Authors: No reported disclosures

P-1506. In Vitro Activity of Ceftazidime-Avibactam and Comparator Agents against Pseudomonas aeruginosa Collected from Patients with Presumed Hospital- and Community-acquired Respiratory Tract Infections as a Part of the ATLAS Global Surveillance Program 2018-2022

Abstract Background The β-lactamase inhibitor, avibactam, has potent inhibitory activity against Class A, Class C, and some Class D serine β-lactamases. This study evaluated the in vitro activity of ceftazidime-avibactam and comparators against respiratory tract infection (RTI)-associated Pseudomonas aeruginosa isolated from presumed community-acquired (CA; culture started < 48 hours after hospital admission) and hospital-acquired (HA; culture started ≥48 hours post-admission) infections collected from 2018-2022. Methods 13,186 isolates were collected from the lower respiratory tract of patients from 224 medical centers in 57 countries (excluding China and North America). Of these, 8,880 were HA and 4,306 were CA. MICs were determined using CLSI broth microdilution and interpreted using CLSI 2024 breakpoints. Isolates testing nonsusceptible (NS) to meropenem (MEM) were screened by PCR and Sanger sequencing for β-lactamase genes. Results Ceftazidime-avibactam was the most active agent tested against the CA population (92.3% susceptible, MIC90 of 8 µg/mL; Table). Against HA isolates, ceftazidime-avibactam was active against 88.6% (MIC90 of 16 µg/mL). Only amikacin was active against more HA isolates (89.4% susceptible; MIC90 32 µg/mL). Of isolates that were MEM-NS and metallo-β-lactamase (MBL)-negative, 81.0% of HA isolates and 79.5% of the CA isolates were susceptible. Conclusion The in vitro activity of ceftazidime-avibactam against CA and HA organisms infecting the lower respiratory tract indicates that it remains an important option for treating infections including those caused by MEM-NS organisms that do not carry an MBL. Disclosures Henry Li, MS in Biotechnology, Pfizer, Inc.: Advisor/Consultant Mark Estabrook, MS, Pfizer, Inc.: Advisor/Consultant Daniel F. Sahm, PhD, Pfizer, Inc.: Advisor/Consultant

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-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

Stratified annual antibiogram and antimicrobial resistance trend report from a teaching hospital in Hyderabad, India

ABSTRACT Introduction: Antibiograms are a vital tool in healthcare facilities, particularly in guiding empiric antimicrobial treatment. Antibiograms created by aggregating hospital-wide susceptibility data can be misleading and may not be appropriate for different settings in the hospital such as intensive care units, in-patient, and out-patient departments. In this study, we have stratified the antibiogram based on the hospital setting. Materials and Methods: The percentage susceptibility of the most common isolates, stratified by location, to individual antibiotics was calculated based on the CLSI 2022 recommended breakpoints. The breakpoints are interpreted as either susceptible (S) or non-susceptible (NS). Only the isolates that were >30 in number were included in the analysis. Results: A total of 947 first isolates (excluding duplicate isolates) of the common organisms isolated from clinical specimens, including urine, blood, pus, sputum, body fluids, etc., were analysed and described in charts. The most common organisms isolated were Escherichia coli (n = 365), Klebsiella pneumoniae (n = 290), Staphylococcus aureus (n = 135), Pseudomonas aeruginosa (n = 80), and Acinetobacter baumannii (n = 77) in that order. Discussion: A higher prevalence of the overall resistance in the critical care setting of the ICU compared to inpatient (IP) and outpatient (OP) settings is concerning. This could be due to the higher antibiotic usage and selection pressure in ICUs, leading to a greater emergence of resistant strains. There is no denying that the AMR is only on the rise and our data goes on to testify the trend. Conclusion: Ongoing education of prescribers on the appropriate use of antibiograms is essential to ensure optimal therapy and outcomes. Multidisciplinary antimicrobial stewardship programs are vital to accomplishing these goals.

Molecular characterization of clinically isolated Pseudomonas aeruginosa with varying resistance to ceftazidime-avibactam and ceftolozane-tazobactam collected as a part of the ATLAS global surveillance program from 2020 to 2021.

Ceftazidime-avibactam (CZA) and ceftolozane-tazobactam (C/T) are important agents for treating multidrug-resistant P. aeruginosa infections. In this study, we evaluated the molecular characteristics of 300 globally collected clinical P. aeruginosa isolates non-susceptible (NS) to CZA, C/T, or both agents. Isolates were CZA-NS and C/T-NS (n = 57), CZA-susceptible (S) and C/T-NS (n = 145), or CZA-NS and C/T-S (n = 98) selected from the Antimicrobial Testing Leadership and Surveillance (ATLAS) surveillance program from 2020 to 2021. Characterization was by whole-genome sequencing. Analysis was performed to identify β-lactamase genes and mutations that impact efflux regulation, AmpC regulation, and target binding (PBP3). Of the 57 CZA-NS+C/T-NS isolates, 64.9% carried a metallo-β-lactamase (MBL), and a cumulative 84.2% carried any non-intrinsic β-lactamase [i.e., not Pseudomonas-derived cephalosporinase (PDC) or OXA-50-like]. Of the 145 CZA-S+C/T-NS isolates, 26.2% carried an extended-spectrum β-lactamase (ESBL) and no carbapenemase, 17.9% carried a serine-carbapenemase, and 42.1% were negative for non-intrinsic β-lactamases. Of 98 CZA-NS+C/T-S isolates, 34.7% carried mutations previously described as causing an upregulation of the MexAB-OprM efflux pump, while only 9.2% carried a non-intrinsic β-lactamase, and no resistance mechanism was identified in 29.6% of these isolates. MBLs were present in most isolates NS to both agents. More than half of the CZA-S+C/T-NS isolates carried serine β-lactamases. The most frequently identified resistance mechanism identified in CZA-NS+C/T-S isolates was a marker indicating the upregulation of MexAB-OprM. No mechanism was identified that is thought to support resistance to these agents in numerous isolates. This may be due in part to the fact that whole genome sequencing (WGS) cannot directly measure gene expression of chromosomal resistance mechanisms.

Population Analysis of Daptomycin-non-Susceptible Methicillin-Resistant Staphylococcus aureus Reveals the Presence of Variants That Contribute to Daptomycin Resistance.

In this study, population analysis (PA) of methicillin-resistant Staphylococcus aureus (MRSA), before and after long-duration daptomycin (DAP) treatment, was used to detect subpopulations with different susceptibilities to DAP and to verify the changes in the number of resistant cells. Furthermore, we aimed to characterize the bacteriology of the variants present in the non-susceptible cell subpopulation. A DAP non-susceptible (NS) MRSA phenotype (D2) that emerged from a DAP- susceptible MRSA phenotype (D1) during treatment of an open wound, was used for testing. We performed bacteriological and genetic analyses of cryptic DAP-NS MRSA variants detected by PA to study the variants present in the resistant cell subpopulation. PA results suggest that MRSA adapted to survival in the presence of DAP are selected leading to reduced susceptibility. Within the cell population growing in media containing 2.0mg/L of DAP, three variants with different pigment production and colony size were detected. Variant 3 was an orange colony due to enhanced production of staphyloxanthin. Our results revealed that the DAP minimum inhibitory concentration (MIC) value increased two-fold (4mg/L) in variant 3, in which pigment production was most enhanced, compared to the parental strain D2. In conclusion, our results indicate that long-duration DAP treatment can lead to the emergence and increased proportion of DAP-NS subpopulations. Furthermore, slow-growing variants that can be detected only under antimicrobial selective pressure are present among DAP-NS cells, suggesting that these variants may also contribute to the development of DAP resistance.

Seasickness susceptibility and the vestibular time constant: a prospective study.

Human passive motion during boat, car or airplane travel may trigger motion sickness. Seasickness is the most provoking manifestation of motion sickness. It imposes major constraints on quality of life and human performance. Based on seasickness susceptibility the population is usually categorized into susceptible (S) and non-susceptible (NS). During repeated exposure some susceptible individuals undergo habituation and obtain symptoms relief, reflecting a third group of habituating (H) individuals. Recently, accumulative evidence suggests that the vestibular time constant (Tc) is associated with motion sickness susceptibility and attenuation of symptoms. These studies demonstrated that repeated passive motion stimuli lead to temporary short-term (days) changes in Tc, whereas sea sickness habituation process lasts 3 to 6months. Therefore, the goal of the present study was to examine the behavior of Tc during the entire span of the seasickness habituation process between the H, S and NS groups to find an objective test for seasickness severity prediction. Tc of 30 subjects was prospectively evaluated pre, 3 and 6months post exposure to sea environment using a computerized rotatory chair system protocol. Seasickness severity was evaluated by Wiker questionnaire. Significantly shorter Tc was found in the S group compared with the NS and H groups. Further analysis revealed lower maximal Slow Phase Velocity (mSPV) and nystagmus frequency (total number of beats/second) in the S group. Our results suggest that Tc, mSPV and nystagmus frequency might serve as a prediction for seasickness severity. This study was retrospectively registered on December 7th 2022 and assigned the identifier number NCT05640258.

722. Risk Factors for Infection or Colonization with Ceftolozane/Tazobactam Non-Susceptible Extensively β-Lactam Resistant Pseudomonas aeruginosa

Abstract Background Treatment of infections due to multidrug resistant (MDR) Pseudomonas aeruginosa is complicated by co-resistance amongst traditional anti-pseudomonal β-lactams, as 50% of MDR isolates exhibit extensive β-lactam resistance (EBR, non-susceptible to cefepime, ceftazidime, piperacillin/tazobactam, and meropenem). Ceftolozane/tazobactam (C/T) was developed to combat MDR and EBR P. aeruginosa. Unfortunately, C/T resistance has proliferated. We designed this retrospective case-control study to identify risk factors for C/T non-susceptibility (NS) amongst EBR P. aeruginosa. Methods Between 2015 to 2020, hospitalized adult patients infected or colonized with EBR P. aeruginosa were identified. C/T susceptibility was defined per the 2023 Clinical and Laboratory Standards Institute (CLSI) guidelines (susceptible (S) if minimum inhibitory concentration (MIC) ≤ 4 mg/L, NS if MIC ≥ 8 mg/L). Patients with an EBR P. aeruginosa NS to C/T were classified as cases, whereas those with S isolates were controls. Patients with multiple EBR P. aeruginosa isolates over the study period were only included once. If a patient had a C/T NS isolate, they were classified as cases and the first C/T NS isolate was included as the index culture. If the patient did not have a C/T NS isolate over the study period, they were considered a control and the first C/T S isolate was the index culture. Bivariate and multivariate modeling was performed to identify independent predictors for C/T NS. Results 188 unique patients with C/T susceptibility performed were included in the study; 96 (51%) were C/T NS and 92 (49%) were C/T S. Table 1 shows the bivariate comparisons of key baseline characteristics between groups. Independent predictors of C/T NS are displayed in table 2. Conclusion Independent predictors for C/T NS amongst EBR P. aeruginosa isolates were a history of cancer, cystic fibrosis, and isolation of EBR P. aeruginosa in the past 90 days. While receipt of cefepime or ceftazidime in the past 90 days was associated with C/T NS in bivariate comparisons, the association did not remain in multivariate modeling. C/T exposure was not a statistically significant risk factor, but it was numerically associated with NS and the lack of significance was likely due to the small number of patients (n = 15) who received it. Disclosures Virginia M. Pierce, MD, FIDSA, UpToDate, Inc.: Authorship royalties jason M. Pogue, PharmD, AbbVie: Advisor/Consultant|Entasis: Advisor/Consultant|Ferring: Advisor/Consultant|GSK: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Qpex: Advisor/Consultant|Shionogi: Advisor/Consultant

2838. Clinical Application and Validation of a Predictive Antimicrobial Resistance Risk Categorization Framework for Patients with Uncomplicated Urinary Tract Infection

Abstract Background Empiric antibiotic (ABX) treatment for uncomplicated urinary tract infections (uUTIs) can be ineffective due to antimicrobial resistance (AMR). Understanding the risk of AMR using data-driven approaches can inform appropriate ABX selection. We developed an AMR pathogen risk categorization framework in E. coli caused uUTI using predictive modeling and evaluated its clinical validity. Methods Eligible females with uUTI confirmed by positive E. coli urine culture treated with nitrofurantoin (NTF), trimethoprim/sulfamethoxazole (SXT), fluoroquinolones (FQs), or beta-lactams (BLs) were identified from the Optum de-identified electronic health record data set (Oct 2015–Feb 2020). We developed predictive models using machine learning to quantify AMR probability for each ABX class. A framework with 3 risk categories (low, moderate, high) was constructed using the predicted probability (PP) of non-susceptibility (NS) (Table 1). Six patient profiles from differing risk categorizations were reviewed for clinical validity by 5 clinicians (4 medical doctors, 1 pharmacist). Results Of 87,487 eligible patients, approximately half were classified as low or high risk (44.0–49.1% across ABX classes). The proportion of patients with infections due to NS organisms was 5–12-fold higher among patients classified as high or moderate vs low risk (Figure 1). After review of the patient profiles (Table 2), clinical experts confirmed the consistency of modeled risk classification for all 6 patients with their own assessment of AMR risk across all drug classes. Patient 1 was aged 20 yrs, White, West residence, no UTI or ABX history 1 year prior to her uUTI; PP of NS was low (NTF 1.5%, SXT 16.6%, FQs 4.8%, BLs 8.4%) and was classified as low risk for all ABX classes. In contrast, patient 6 was post-menopausal, Black, Midwest residence, and had UTI episodes, prior AMR, and multiple healthcare visits 1 year prior to uUTI. She had high PP of NS (NTF 10.3%, SXT 97.2%, FQs 96.4%, BLs 48.0%) and was categorized as high risk for all ABX classes. Conclusion AMR risk varied greatly between patients. Our prediction model contextualizes patients’ AMR PP to 4 commonly prescribed ABX classes in the setting of uUTIs. Clinical application of this framework could inform appropriate empiric ABX selection for patients with uUTI. Disclosures Ryan K. Shields, PharmD, MS, Allergan: Advisor/Consultant|Cidara: Advisor/Consultant|Entasis: Advisor/Consultant|GSK: Advisor/Consultant|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Menarini: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Roche: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Utility: Advisor/Consultant|Venatorx: Advisor/Consultant|Venatorx: Grant/Research Support Wendy Y. Cheng, MPH, PhD, ORCID: 0000-0002-8281-2496, Analysis Group, Inc.: Wendy Y. Cheng is an employee of Analysis Group, Inc., a consulting company that received funding from GSK to conduct this study Kalé Kponee-Shovein, ScD, Analysis Group, Inc: Employee of Analysis Group, Inc., which received funding from GSK to conduct the study Fernando Kuwer, MSc, Analysis Group, Inc.: Employee of Analysis Group, Inc., which received funding from GSK to conduct the study Chi Gao, ScD, Analysis Group, Inc.: Employee of Analysis Group, Inc., which received funding from GSK to conduct the study Ashish V. Joshi, PhD, GSK: Employee|GSK: Stocks/Bonds Fanny S. Mitrani-Gold, MPH, GSK: Employee|GSK: Stocks/Bonds Patrick Schwab, PhD, GSK: Employment|GSK: Stocks/Bonds Diogo Ferrinho, PharmD, GSK: Employee|GSK: Stocks/Bonds Malena Mahendran, MS, Analysis Group, Inc.: Malena Mahendran is an employee of Analysis Group, Inc., a consulting company that received funding from GSK to conduct this study Daniel Indacochea, PhD, Analysis Group, Inc.: Employee of Analysis Group, Inc., which received funding from GSK to conduct the study Lisa Pinheiro, MFin, Analysis Group, Inc.: Employee of Analysis Group, Inc., which received funding from GSK to conduct the study Jimmy Royer, PhD, Analysis Group, Inc.: Employee of Analysis Group, Inc., which received funding from GSK to conduct the study Madison T. Preib, MPH, GSK: Employee|GSK: Stocks/Bonds Jennifer Han, MD, GSK: Employment|GSK: Stocks/Bonds Richard Colgan, MD, GSK: Advisor/Consultant

2154. Cross-resistance of Ceftolozane-Tazobactam and Imipenem-Relebactam Against Clinical P. aeruginosa Isolates from Bloodstream and Respiratory Tract Infections– SMART United States 2019-2021

Abstract Background Antimicrobial resistance among Pseudomonas aeruginosa is challenging with limited treatment options. Ceftolozane/tazobactam (C/T) maintains activity against P. aeruginosa resistant to commonly used β-lactams. Imipenem/relebactam (IMI/REL) can restore the activity of IMI against P. aeruginosa. C/T and IMI/REL can be affected by different mechanisms of resistance, and pathogens can be nonsusceptible to one agent but susceptible to the other. We evaluated the activity of C/T and IMI/REL against P. aeruginosa isolates collected from patients with lower respiratory tract (LRTI) and bloodstream (BSI) infections in the United States as part of the global SMART surveillance program. Methods In 2019-2021, 24 US clinical labs collected up to 100 consecutive, aerobic or facultative, gram-negative pathogens from LRTI and up to 50 from BSI. Of 8643 collected isolates, 1986 (23%) were P. aeruginosa. Susceptibility was determined with CLSI broth microdilution and 2023 CLSI breakpoints. Results Among P. aeruginosa BSI and LRTI isolates, 88% were susceptible (S) to both C/T and IMI/REL, 2% were nonsusceptible (NS) to both agents; 8% were S to C/T but not to IMI/REL, and 2% were S to IMI/REL but not to C/T (Table 1). Among MDR and DTR isolates, 45% and 29%, respectively, were S to both C/T and IMI/REL and 11% and 20%, respectively, were NS to both. Among C/T-NS isolates, 57.3% and 44.0% were S to IMI/REL and ceftazidime/avibactam (CZA), respectively (Table 2). Among IMI/REL-NS isolates, 83% were C/T-S, 69% CZA-S, and < 43% were S to all other studied β-lactams and LVX. Among CZA-R isolates, 61% and 47% remained S to C/T and IMI/REL, respectively. Conclusion Resistance to both C/T and IMI/REL was not common among recent clinical isolates of P. aeruginosa from the US, and both agents represent important treatment options. A significant proportion of isolates NS to one agent were S to the other, especially among MDR and DTR isolates. The data suggest that susceptibility to both agents should be tested. Disclosures Sibylle Lob, MD, Merck & Co., Inc.: Honoraria Mark G Wise, PhD, Merck & Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation Fakhar Siddiqui, MD, MBA, Merck & Co Inc.: Employee Daniel F. Sahm, PhD, Merck & Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation

1949. Activity of Aztreonam-Avibactam against Enterobacterales Resistant to Recently Approved Beta-Lactamase Inhibitor Combinations Collected Worldwide (ex-US; 2020–2022)

Abstract Background Aztreonam-avibactam (ATM-AVI) is under clinical development. Aztreonam is a monobactam stable to hydrolysis by metallo-β-lactamases (MBLs). ATM-AVI has shown activity against MBL-producing, carbapenem-resistant Enterobacterales (CRE) that are resistant to recently approved β-lactamase inhibitor combinations (BLIs) such as ceftazidime-avibactam (CAZ-AVI), meropenem-vaborbactam (MEM-VAB), and imipenem-relebactam (IMI-REL). We evaluated a large collection of CRE isolates nonsusceptible (NS) to these BLIs. Methods 24,580 Enterobacterales isolates were consecutively collected (1/patient) in 2020–2022 from 64 medical centers located in Western Europe (W-EU; 27 centers in 10 countries), Eastern Europe (E-EU; 13 centers in 9 countries), Latin America (LATMA; 8 centers in 6 countries), and the Asia-Pacific region (APAC; 16 centers in 8 countries). Among these isolates, 1,016 (4.1%) were CRE. Isolates were susceptibility tested by CLSI broth microdilution. CRE isolates were screened for carbapenemase (CPE) genes by whole genome sequencing. Results ATM-AVI inhibited 99.6% of CREs (MIC50/90, 0.25/0.5 mg/L) and ≥ 98.9% of CRE isolates NS to CAZ-AVI, MEM-VAB, and/or IMI-REL at ≤8 mg/L (Table). The most active comparators against CREs were CAZ-AVI (64.6%S), MEM-VAB (57.4%S), and IMI-REL (50.7%S). The activity of these BLIs varied widely among region, with highest susceptibility rates observed in W-EU (76.9% for CAZ-AVI, 72.5% for MEM-VAB, 63.8% for IMI-REL), followed by LATAM (65.1% for CAZ-AVI, 70.6% for MEM-VAB, 62.8% for IMI-REL), E-EU (66.6% for CAZ-AVI, 46.7% for MEM-VAB, 43.5% for IMI-REL), and APAC (39.9% for CAZ-AVI, 37.8% for MEM-VAB, 27.7% for IMI-REL). The most common CPE types overall were KPC (44.5% of CREs), NDM (29.8%), and OXA-48-like (16.0%). KPC predominated in LATAM (64.1%) and W-EU (61.1% of CREs). MBL occurrence was highest in APAC (59.5% of CREs), followed by LATAM (34.0%), E-EU (28.9%), and W-EU (23.6%). NDM represented 85.4% of MBLs. Conclusion ATM-AVI demonstrated potent activity against CRE isolates resistant to CAZ-AVI, MEM-VAB, and/or IMI-REL independent of the CPE produced. The activity of recently approved BLIs varied broadly among regions and were very limited in E-EU and APAC. Disclosures Helio S. Sader, MD, PhD, FIDSA, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Entasis: Grant/Research Support|Melinta: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Leonard R. Duncan, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|CorMedix: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support John H. Kimbrough, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Cecilia G. Carvalhaes, MD, PhD, AbbVie: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: 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

2146. Antimicrobial Activity of Aztreonam-avibactam, Ceftazidime-avibactam, and Meropenem-vaborbactam against Enterobacterales causing Bloodstream Infection in US Medical Centers (2020–2022)

Abstract Background As the frequency of Enterobacterales (ENT) producing metallo-β-lactamase (MBL) and/or OXA-48 is increasing in some US medical centers, effective antimicrobials to treat the infections caused by these organisms are urgently needed. Aztreonam-avibactam (ATM-AVI) is under clinical development for treatment of infections caused by Gram-negative bacteria, including MBL producers. We evaluated the activities of ATM-AVI, ceftazidime-avibactam (CAZ-AVI), meropenem-vaborbactam (MEM-VAB), and comparators against ENT isolated from patients with bloodstream infections (BSIs). Methods 4,802 ENT were consecutively collected (1/patient) from 72 US medical centers in 2020–2022 and susceptibility tested by CLSI broth microdilution method. ATM-AVI was tested with AVI at a fixed 4 mg/L. A pharmacokinetic/pharmacodynamic susceptible (S) breakpoint of ≤ 8 mg/L was applied for comparison. Carbapenem-resistant ENT (CRE) isolates were screened for carbapenemase (CPE) by whole genome sequencing. Results ATM-AVI was highly active against ENT (Table); only 2 isolates showed ATM-AVI MICs > 8 mg/L: 1 MEM-S E. coli and 1 E. aerogenes (CRE). All CPE producers and 98.0% of CREs were inhibited at an ATM-AVI MIC of ≤ 8 mg/L. CAZ-AVI and MEM-VAB were active against 81.6% and 65.3% of CREs, respectively. Ceftolozane-tazobactam (TOL-TAZ) was active against only 72.6% of ceftriaxone (CRO)-nonsusceptible (NS) isolates. ATM-AVI retained activity (MIC, ≤8 mg/L) against all MEM-VAB-NS and 90.0% of CAZ-AVI-NS isolates. The most common CPEs were KPC-2/3 (57.1% of CREs), OXA-48–like (16.3%), and NDM (12.2%). A CPE gene was not observed in 14.3% of CREs. CAZ-AVI and MEM-VAB were active against 100.0% of KPC producers, but CAZ-AVI showed limited activity against MBL producers and MEM-VAB showed limited activity against OXA-48–like and MBL producers. The most active comparators against CRE were tigecycline (95.9%S), gentamicin (49.0%S), and amikacin (44.9%S). Conclusion ATM-AVI demonstrated potent activity against a large collection ENT isolated from patients with BSI in US hospitals, including CREs and isolates resistant to recently approved β-lactamase inhibitor combinations. These results support further clinical development of ATM-AVI. Disclosures Helio S. Sader, MD, PhD, FIDSA, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Cecilia G. Carvalhaes, MD, PhD, AbbVie: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support John H. Kimbrough, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: 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 Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Entasis: Grant/Research Support|Melinta: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support