Treatment options for Carbapenem-resistant (CR) Gram-negative infections due to metallo-beta-lactamase (MBL) enzymes are limited. The clinical impact of MBLs vs. other mechanisms of carbapenem resistance in Enterobacterales and non-fermenting bacteria remains unclear.Table 1.Demographics, isolate characteristics, and outcomes of patients with carbapenem-resistant Gram-negative infections, stratified by MBL statusFigure 1.30-day desirability of outcome ranking (DOOR) outcomes of patients with carbapenem-resistant Gram-negative infections, stratified by MBL statusCRPA – carbapenem-resistant Pseudomonas aeruginosa, CRAb – carbapenem-resistant Acinetobacter baumannii, CRE – carbapenem-resistant Enterobacterales, DOOR – desirability of outcome ranking. MBL – metallo-beta-lactamase. DOOR events assessed at 30 days include: unsuccessful discharge, lack of clinical response, and C. difficile infection and/or renal failure. Not all rows total to 100 due to rounding. P-value calculated using Wilcoxon test. We conducted a matched cohort study of patients enrolled in one of three MDRO Network studies, POP (CR Pseudomonas aeruginosa [CRPA]), SNAP (CR Acinetobacter baumannii [CRAb]), or CRACKLE-2 (CR-Enterobacterales [CRE]) with isolates that met infection criteria. Patients with MBL-producing isolates (blaVIM, blaIMP, or blaNDM present) were matched 1:2 to patients with non-MBL CR isolates (a different carbapenemase or CR without a carbapenemase) based on study, region, and anatomical source. We compared baseline characteristics, 30- and 90-day mortality, and 30-day desirability of outcome ranking (DOOR) scores.30-day Desirability of Outcome Ranking (DOOR) Probability by MBL StatusLegend: CI – confidence interval, CRPA – carbapenem-resistant Pseudomonas aeruginosa, CRAb – carbapenem-resistant Acinetobacter baumannii, CRE – carbapenem-resistant Enterobacterales, DOOR – desirability of outcome ranking. MBL – metallo-beta-lactamase. The DOOR probability was calculated as the probability of a more desirable result in the presence of MBL as compared to non-MBL isolate. Confidence intervals were calculated using the method in Halperin et al (Biometric 1989; 45:500-521), and CI’s that do not include 50% are considered statistically significant. Estimates less than 50% signify a less favorable outcome for the MBL group, while estimates greater than 50% signify more favorable outcomes for the MBL group. In total, 170 MBL isolates were matched to 340 non-MBL isolates from 10 countries (Table 1). The cohort included 42% CRPA (216/510), 5% CRAb (24/510), and 53% CRE (270/510). Demographics were balanced between groups; median age at culture was 61 (Q1, 44, Q3 73) years. Common infection sources were respiratory (151/510, 30%), urine (141/510, 28%), and blood (105/510, 21%). Of the MBL isolates, 92/170 harbored blaNDM (54%), 62/170 harbored blaVIM (36%), and 20/170 harbored blaIMP (12%); four isolates co-harbored two distinct MBL enzymes. All-cause 30-day mortality was 19% (33/170) for MBL vs 18% (61/340) for non-MBL (p=0.69); MBL presence was not associated with 30- or 90-day mortality. DOOR outcomes at 30-days (Figure 1) did not differ by MBL status in the full cohort or the CRE subgroup, but did differ in the CRPA/CRAb subgroup (p=0.037). Among CRPA/CRAb infections, MBL presence was associated with less desirable outcomes (DOOR probability 42.1%; 95% Halperin confidence interval: 35.0%-49.5%, Figure 2). MBL presence was not associated with increased 30- or 90-day mortality compared to matched non-MBL isolates. However, in non-fermenter infections (CRPA/CRAb), MBL presence was linked to less desirable outcomes, an association not seen in CRE. These findings may inform prioritization of anti-MBL agents in future drug development. Angelique E. Boutzoukas, MD, MPH, Elion Therapeutics: Advisor/Consultant|Innoviva Speciality Therapeutics: DSMB Participant Souha S. Kanj, MD, Menarini: Honoraria|pfizer: Honoraria Vance G. Fowler, MD, MHS, Affinergy, Janssen, Contrafect: Advisor/Consultant|AstraZeneca; EDE; Basilea: Grant/Research Support|Debiopharm, GSK; Affinium, Basilea,: Advisor/Consultant|Destiny, Amphliphi, Armata, Akagera: Advisor/Consultant|Merck; Contrafect; Karius; Janssen: Grant/Research Support|UpToDate: Royalties|Valanbio: Stock options Yohei Doi, MD, PHD, GSK: Advisor/Consultant|Meiji Seika Pharma: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Honoraria Michael Satlin, MD, MS, AbbVie: DSMB Participant|bioMerieux: Grant/Research Support|Merck: Grant/Research Support|SNIPRBiome: Grant/Research Support Robert A. Bonomo, MD, Merck: Grant/Research Support|Shinogi: Grant/Research Support|VenatoRx: Grant/Research Support David van Duin, MD, PhD, British Society for Antimicrobial Chemotherapy: Editor stipend|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Roche: Advisor/Consultant|Shionogi: Advisor/Consultant

The spread and rise of antimicrobial resistance poses a risk to public health due to limited effective treatment options. Alternative antimicrobials that are effective against gram-negative multi-drug resistant pathogens. The increasing rate of carbapenem resistance observed in Klebsiella pneumoniae , indicates the need for alternative antimicrobial options. Bacteriophages that target Klebsiella pneumoniae are promising alternative antimicrobial option, with successful treatments being reported. Here we characterized 30 lytic bacteriophages from various environmental sources and tested their effectiveness against nine clinically relevant carbapenem-resistant K. pneumoniae isolates. These phages were characterized through genomic sequencing, bioinformatic analysis, virulence in liquid medium, and host range on different mediums. Bioinformatic analysis revealed a diverse collection of phages that span 9 ICTV recognized families and 13 genera with genome sizes ranging from 39-349 kbp. The phages were able to inhibit bacterial growth, and no virulence or antibiotic resistance genes were detected within the phage genomes. Host range testing demonstrated phages with broad host range have varying infectivity when plated on different common growth mediums. This study includes candidate phages for further potential development as potential antimicrobial agents against CR-KP, and the complexity in understanding phage-host dynamics of non-capsule phages that target against K. pneumoniae .

BACKGROUND:Despite the global public health threat posed by carbapenem-resistant Enterobacter spp, clinical and molecular epidemiological studies on international isolates remain scarce. Historically, the taxonomy of Enterobacter has been challenging, limiting our understanding of the clinical characteristics and outcomes of carbapenemase-producing Enterobacter spp infections. METHODS:Hospitalized patients enrolled in the CRACKLE-2 study (ClinicalTrials.gov, NCT03646227) from 2016 to 2018 with cultures positive for carbapenemase-producing Enterobacter spp were included. Clinical and microbiologic data were collected from health records. Whole genome sequencing was performed, and the population structures of selected predominant clones were analyzed. RESULTS:We enrolled 136 hospitalized patients with carbapenemase-producing Enterobacter spp from 30 hospitals in 7 countries. Among the 136 isolates, 11 Enterobacter spp were identified, with most isolates belonging to E xiangfangensis (n = 81 [60%]) and E hoffmannii (n = 17 [13%]) and carrying blaKPC (n = 106 [78%]) and blaNDM (n = 12 [9%]). Clinical characteristics and outcomes were similar among patients with E xiangfangensis, E hoffmannii, or the other Enterobacter spp. Thirty-day mortality was 20%, and older age at enrollment (adjusted odds ratio, 1.42 [95% confidence interval, 1.08-1.87]) was associated with increased mortality. Sequence type (ST) 171 E xiangfangensis, ST78 E hoffmannii, and ST93 E xiangfangensis were the predominant clones, and the acquisition of fluoroquinolone resistance-associated mutations and carbapenemase-encoding plasmids contributed to their formation and global dissemination. CONCLUSIONS:Our findings demonstrate that E xiangfangensis and E hoffmannii are common species among international carbapenemase-producing Enterobacter spp, potentially linked to the clonal spread of a few predominant clones that have acquired fluoroquinolone resistance and carbapenemase-encoding plasmids.

Currently available rapid blood culture diagnostics detect few gram-negative resistance determinants, limiting their clinical utility. We prospectively evaluated the prototype BIOFIRE FILMARRAY Antimicrobial Resistance (AMR) Panel, a rapid multiplex PCR test that detects 31 AMR genes, on residual positive blood culture broths from patients with gram-negative bacteremia due to five target organisms at a New York City hospital. Predicted antimicrobial resistance based on the AMR Panel was compared to results from broth microdilution testing of bloodstream isolates recovered in culture. A simulated stewardship study assessed opportunities for the optimization of therapy if the AMR Panel results had been available for patient care in real time. We enrolled 148 patients with gram-negative bacteremia (Escherichia coli, n = 75; Klebsiella pneumoniae, n = 44; Pseudomonas aeruginosa, n = 17; Enterobacter cloacae complex, n = 9; and Acinetobacter baumannii, n = 3). The sensitivity of the AMR Panel for predicting antimicrobial resistance was ≥90% for 10/14 antimicrobial agents in E. coli and for 10/16 agents in K. pneumoniae. Specificity was ≥90% for 15/17 agents in E. coli and for all 16 agents in K. pneumoniae. Performance for other organisms was poor. For E. coli or K. pneumoniae bacteremia, use of the AMR Panel could have led to earlier escalation or de-escalation of β-lactam therapy in a majority of patients compared to what actually occurred. This study demonstrates that a rapid multiplex PCR test with a large menu of AMR genes can be applied to positive blood culture broths to rapidly predict resistance to frontline antimicrobial agents in patients with E. coli or K. pneumoniae bacteremia.IMPORTANCEPatients with gram-negative bacteremia require urgent treatment with antimicrobial agents that are effective against their infecting pathogen. However, conventional laboratory work-up of blood cultures takes days to yield results, and during this time, patients may receive ineffective therapies. We evaluated the prototype BIOFIRE FILMARRAY AMR Panel, an assay that detects 31 genes in gram-negative bacteria that confer resistance to β-lactams, fluoroquinolones, and aminoglycosides in approximately 1 hour, directly from positive blood culture broths, and compared these results to antimicrobial susceptibility testing of isolates recovered in culture. We found that the AMR Panel accurately predicted resistance in Escherichia coli and Klebsiella pneumoniae to most antimicrobials. Moreover, if results from this assay had been used for patient care, there would have been opportunities to optimize antimicrobial prescribing more quickly than using conventional methods. These data demonstrate how novel molecular assays could optimize care for patients with E. coli and K. pneumoniae bacteremia.

Abstract Background CACTUS is a retrospective, matched, multicenter study comparing the efficacy of C/T and CZA for the treatment of bacteremia or pneumonia due to MDR P. aeruginosa. We previously demonstrated that treatment with C/T resulted in higher rates of clinical success compared to CZA. The objective of this analysis is to compare the day 30 Desirability of Outcome Ranking (DOOR) between matched patient pairs. Methods C/T and CZA patients were matched 1:1 within each study site based on severity of illness, infection type, and time to treatment initiation. The DOOR scale applied is described in Figure 1. Each matched pair was compared for a better ranking. The frequency of an improved DOOR for C/T compared to CZA was determined for the entire cohort (n = 210 pairs) and pneumonia subgroup (n = 175 pairs) where a DOOR of 50% would represent no difference. In addition, we measured the magnitude of DOOR differences within matched pairs. Results C/T was not associated with an improved DOOR relative to CZA in the overall cohort (53.3% (95% CI 47.2 – 59.4)) or pneumonia subgroup (54.6% (95% CI 47.9 – 61.2); Figure 1). Specifically, 37% of pairs had the same DOOR, 33% had a lower (better) DOOR with C/T, and 30% had a lower DOOR with CZA. Figure 2 shows the magnitude of DOOR differences for patient pairs. The magnitude was greater for pairs when C/T was associated with a better outcome as compared to the magnitude for pairs when CZA was associated with a better outcome. This difference was more pronounced among patients with pneumonia (Figure 3). A summary of major comparisons is shown in Figure 4. For the entire cohort, an improved DOOR by ≥2 categories within matched pairs occurred more commonly with C/T vs. CZA (p=0.03). In the subgroup of patients with pneumonia, a greater proportion of pairs showed the greatest possible difference (success without complications (DOOR=1) versus death (DOOR=5)) in favor of C/T compared to pairs in favor of CZA; 14% vs. 7%; p = 0.06. Conclusion These data demonstrate the power of matched data for analyzing DOOR endpoints. While there was no difference in the overall DOOR, the magnitude of improved outcomes consistently favored C/T over CZA and suggests clinically important differences in these agents for patients with MDR P. aeruginosa pneumonia or bacteremia. Disclosures jason M. Pogue, PharmD, Entasis: Advisor/Consultant|GSK: Advisor/Consultant|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Venatorx: Advisor/Consultant Samuel L. Aitken, PharmD, MPH, Basilea: Advisor/Consultant|bioMerieux: Advisor/Consultant|Melinta: Advisor/Consultant|Shionogi: Advisor/Consultant Ahmed Babiker, MBBS, Beckman Coulter Inc.: Advisor/Consultant Kimberly C. Claeys, PharmD, PhD, bioMérieux: Advisor/Consultant|bioMérieux: Honoraria Kate DeSear, PharmD, BCIDP, AAHIVP, FIDSA, AbbVie Inc: Advisor/Consultant|Basilea Pharmaceutica: Advisor/Consultant|GSK: Advisor/Consultant|La Jolla (Entasis): Advisor/Consultant|Melinta Therapuetics: Advisor/Consultant Alan E. Gross, PharmD, Becton Dickinson Co: Advisor/Consultant Keith S. Kaye, MD, MPH, Allecra: Advisor/Consultant|CARB-X: Advisor/Consultant|GSK: Advisor/Consultant|Merck: Advisor/Consultant|Shionogi: Advisor/Consultant|Spero: Advisor/Consultant Wesley D. Kufel, Pharm.D., BCPS, BCIDP, Merck & Co.: Grant/Research Support|Shionogi, Inc: Grant/Research Support Conan MacDougall, PharmD, MAS, Merck: Grant/Research Support Erin K. McCreary, PharmD, Abbvie: Advisor/Consultant|Basilea: Advisor/Consultant|Ciadara: Advisor/Consultant|Entasis: Advisor/Consultant|Ferring: Advisor/Consultant|GSK: Advisor/Consultant|GSK: Honoraria|Melinta: Advisor/Consultant|Merck: Advisor/Consultant|Pfizer: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Honoraria William R. Miller, M.D., Merck: Grant/Research Support|UptoDate: Royalties Jeffrey C. Pearson, PharmD, inflarx: 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 David van Duin, MD, PhD, Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Qpex: Advisor/Consultant|Roche: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support 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

Abstract Background Hematopoietic cell transplant (HCT) recipients and patients with acute leukemia are at high risk of Gram-negative bacteremia during neutropenia. Fluoroquinolone (FQ) prophylaxis is used to prevent bacterial infections during neutropenia, but the impact of colonization with FQ-resistant Enterobacterales (FQRE) on its effectiveness is unclear. Methods Adult patients undergoing HCT or receiving induction chemotherapy for acute leukemia were enrolled at 10 U.S. centers from 2021 to 2023. Patients received FQ prophylaxis during neutropenia. Perianal swabs were collected within 4 days of initiating chemotherapy or during the week before HCT, and underwent selective broth enrichment culture for FQRE. Isolates underwent antimicrobial susceptibility testing by disk diffusion. Risk factors for FQRE colonization were identified and infections prior to neutrophil recovery were compared between FQRE-colonized and non-colonized patients. Results Among 784 patients (376 allogeneic HCT recipients, 291 autologous HCT recipients, and 117 receiving chemotherapy for acute leukemia), 81 (10.3%) were colonized with FQRE. Risk factors for FQRE colonization were non-White race, prior HCT, receipt of a β-lactam or any antibacterial agent within last 3 months, and having prior detection of FQRE or a 3rd-generation cephalosporin-resistant Enterobacterales (Table 1). Of the 87 colonizing FQRE isolates (Escherichia coli: n=71; Klebsiella pneumoniae: n=12), 33% were susceptible to trimethoprim-sulfamethoxazole, 53% to amoxicillin-clavulanate, and 66% to cefpodoxime (Figure 1). FQRE-colonized patients had increased risk of bloodstream infections (BSIs) due to any Gram-negative bacteria (28.4% vs. 3.6%; p< 0.001) and FQRE (23.5% vs. 1.6%; p< 0.001) compared to non-colonized patients (Figure 2). They also had an increased risk of infections other than BSIs (12.3% vs. 4.0%; p=0.003) and intensive care unit admissions (12.3% vs. 4.2%; p=0.005) prior to neutrophil recovery, but similar 90-day mortality (4.9% vs. 4.0%, p=0.6). Conclusion Screening for FQRE colonization identifies patients at high risk of Gram-negative bacteremia following FQ prophylaxis. Alternate infection prevention strategies are needed in FQRE-colonized patients. Disclosures Catherine Liu, MD, Pfizer: Grant/Research Support Sarah B. Doernberg, MD, MAS, Basilea Pharmaceutica: Grant/Research Support|F2G Limited: Grant/Research Support|Genentech: Advisor/Consultant|Gilead Biosciences: Grant/Research Support|Janssen/J+J: Advisor/Consultant|Pfizer, Inc: Grant/Research Support|Regeneron, Inc: Grant/Research Support|Shinogi: Grant/Research Support Scott D. Rowley, MD, COTA: Stocks/Bonds (Private Company)|Genetic Testing Cooperative: Stocks/Bonds (Private Company)|SirPant Immunotherapeutics: Advisor/Consultant 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 David van Duin, MD, PhD, Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Qpex: Advisor/Consultant|Roche: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support Samantha E. Jacobs, MD, MS, Ansun Biopharma: Advisor/Consultant|Eurofins, Viracor, LLC.: Grant/Research Support Thomas J. Walsh, MD, PhD (Hon), FIDSA, FAAM, FECMM, Abbott Laboratories: Advisor/Consultant|Basilea: Advisor/Consultant|Basilea: Grant/Research Support|Cape Cod Associates: Advisor/Consultant|F2G: Advisor/Consultant|F2G: Grant/Research Support|Omeros: Advisor/Consultant|Omeros: Grant/Research Support|Partner Therapeutics: Advisor/Consultant|Scynexis: Advisor/Consultant|Scynexis: Grant/Research Support|Statera: Advisor/Consultant|T2 Biosystems: Advisor/Consultant|T2 Biosystems: Grant/Research Support Henry Chambers, MD, Merck: Stocks/Bonds (Private Company)|Moderna: Stocks/Bonds (Private Company) Vance G. Fowler, MD, MHS, Affinergy: Advisor/Consultant|ArcBio: Stocks/Bonds (Private Company)|Armata: Advisor/Consultant|Astra Zeneca: Advisor/Consultant|Astra Zeneca: Grant/Research Support|Basilea: Advisor/Consultant|Basilea: Grant/Research Support|ContraFect: Advisor/Consultant|ContraFect: Grant/Research Support|Debiopharm: Advisor/Consultant|Destiny: Advisor/Consultant|EDE: Grant/Research Support|Genentech: Advisor/Consultant|Genentech: Grant/Research Support|GSK: Advisor/Consultant|Janssen: Advisor/Consultant|Karius: Grant/Research Support|MedImmune: Grant/Research Support|Merck: Grant/Research Support|sepsis diagnostics: Patent pending|UptoDate: Royalties|Valanbuio: Stocks/Bonds (Private Company)|Valanbuio: Stocks/Bonds (Private Company) Lars Westblade, PhD, Accelerate Diagnostics, Inc: Grant/Research Support|bioMerieux, Inc: Grant/Research Support|Element Materials Technology: Grant/Research Support|Hardy Diagnostics: Grant/Research Support|Roche Molecular Systems, Inc.: Advisor/Consultant|Roche Molecular Systems, Inc.: Grant/Research Support|Selux Diagnostics, Inc.: Grant/Research Support|Shionogi, Inc: Advisor/Consultant|Talis Biomedical: 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

Abstract Background Drug-resistant E. coli is a leading cause of antimicrobial resistance-associated deaths globally. Specifically, resistance to ceftriaxone (CRO-R) is increasing in E. coli. High-risk clonal group ST131 and its pandemic H30 subclone are of high concern yet studies characterizing these infections are limited. We evaluated baseline characteristics and clinical outcomes associated with H30 ST131, non-H30 ST131 and non-ST131 E. coli bloodstream infections (BSI). Methods Patients with monomicrobial carbapenem-susceptible E. coli BSI that were matched 1:1 by study site (CRO-R and CRO-susceptible community-acquired and hospital onset cases) were prospectively enrolled from 14 United States hospitals between November 12, 2020 to April 28, 2021 in the multicenter Study of Highly Resistant E. coli (SHREC). Isolates underwent whole genome sequencing. The primary outcome was a 30-day Desirability of Outcome Ranking (DOOR) after index culture including clinical response to treatment and all-cause mortality. Results There were 92 (33%) H30 ST131, 29 (10%) non-H30 ST131, and 161 (57%) non-ST131 isolates in 282 E. coli BSI (Table 1). Most ceftriaxone resistance was conferred by CTX-M-15 produced by H30 ST131 isolates (Figure 1, Table 1). H30 ST131 BSI patients were older (median age [IQR] 70.5 [63,76] vs. 67 [56,77] vs 65 [51,74] years, p = 0.017), had higher Charlson comorbidity indices (3 [2,5] vs. 2 [1,4] vs. 2 [1,4], p=0.009), and were more often admitted from long-term care facilities (18/92 [20%] vs. 3/29 [10%] vs. 7/161 [4%], p = 0.003) compared to non-H30 ST131 and non-ST131 BSI patients. Among H30 ST131 isolates, high rates of antibiotic resistance were observed to cephalosporins and fluoroquinolones, resulting in significantly more carbapenem use compared with non-H30 ST131 and non-ST131 isolates (75/92 [82%] vs. 14/29 [48%] vs. 50/161 [31%], p < 0.001) (Figure 2). 30-day DOOR and hospital length of stay did not differ between groups (Table 2). Conclusion Compared with non-H30 ST131 and non-ST131 E. coli BSI, H30 ST131 E. coli BSI have a unique epidemiology with more healthcare exposures, comorbidities and antibiotic resistance and are more likely to be treated with carbapenems, though no significant difference in clinical outcomes was observed. Disclosures Yohei Doi, MD, PHD, AbbVie: Honoraria|Entasis: Grant/Research Support|Gilead: Advisor/Consultant|GSK: Advisor/Consultant|Meiji Seika: Advisor/Consultant|Moderna: Advisor/Consultant|Pfizer: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Honoraria Elie Saade, MD, MPH, FIDSA, Janssen Global Services: Advisor/Consultant|Janssen Global Services: Advisor/Consultant|Janssen Research and Development: Advisor/Consultant|Janssen Research and Development: Advisor/Consultant Loren G. Miller, MD MPH, Armata: Grant/Research Support|Contrafect: Grant/Research Support|GSK: Grant/Research Support|Merck: Grant/Research Support|Paratek: Grant/Research Support Michael J. Satlin, MD, AbbVie: DSMB participant|bioMerieux: Grant/Research Support|Merck: Grant/Research Support|Selux Diagnostics: Grant/Research Support|SNIPRBiome: Grant/Research Support W. Charles Huskins, MD, MSc, ADMA Biologics: Advisor/Consultant|Bristol Myers Squibb: Stocks/Bonds (Public Company)|Pfizer: Advisor/Consultant|Pfizer: Stocks/Bonds (Public Company)|Zimmer Biomet: Stocks/Bonds (Public Company) Carol Hill, PhD, Glaxo SmithKline: Retirement Health, Cash Balance Plan|Glaxo SmithKline: Stocks/Bonds (Public Company) Robin Patel, MD, a patent on Bordetella pertussis/parapertussis PCR issued, a patent on a device/method for sonication with royalties paid by Samsung to Mayo Clinic, a: See above|MicuRx Pharmaceuticals and BIOFIRE: Grant/Research Support|PhAST, Day Zero Diagnostics, Abbott Laboratories, Sysmex, DEEPULL DIAGNOSTICS, S.L., Netflix, Oxford Nanopore Technologies and CARB-X: Advisor/Consultant|Up-to-Date and the Infectious Diseases Board Review Course.: Honoraria Vance G. Fowler, MD, MHS, Affinergy: Advisor/Consultant|ArcBio: Stocks/Bonds (Private Company)|Armata: Advisor/Consultant|Astra Zeneca: Advisor/Consultant|Astra Zeneca: Grant/Research Support|Basilea: Advisor/Consultant|Basilea: Grant/Research Support|ContraFect: Advisor/Consultant|ContraFect: Grant/Research Support|Debiopharm: Advisor/Consultant|Destiny: Advisor/Consultant|EDE: Grant/Research Support|Genentech: Advisor/Consultant|Genentech: Grant/Research Support|GSK: Advisor/Consultant|Janssen: Advisor/Consultant|Karius: Grant/Research Support|MedImmune: Grant/Research Support|Merck: Grant/Research Support|sepsis diagnostics: Patent pending|UptoDate: Royalties|Valanbuio: Stocks/Bonds (Private Company)|Valanbuio: Stocks/Bonds (Private Company) David van Duin, MD, PhD, Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Qpex: Advisor/Consultant|Roche: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support

Abstract Background CACTUS is a retrospective, matched, multicenter study comparing the efficacy of C/T and CZA for treatment of bacteremia or pneumonia due to MDR P. aeruginosa. We found that treatment with C/T resulted in higher rates of clinical success compared to CZA after controlling for baseline differences between cohorts. The objective of this study is to determine the impact of patient subgroups on the overall findings. Methods C/T and CZA patients were matched 1:1 within each study site based on severity of illness, infection type, and time to treatment initiation. The primary outcome was clinical success at day 30, defined as survival, resolution of signs/symptoms of infection with the intended treatment course, and absence of recurrent infection. For subgroups of interest, the proportion with clinical success in each group was compared using an unadjusted odds ratio (OR) and 95% confidence interval. Results Among 420 cases from 28 sites, 60.95% (128/210) of C/T- and 51.9% (109/210) of CZA-treated patients experienced clinical success. Groups were overall well-balanced by matching; however, CT-treated patients were older, more likely to have immunocompromising conditions, and to receive suboptimal dosing (Table 1). After conditional logistic regression, the adjusted OR for clinical success with C/T treatment was 1.97 (95% CI: 1.11 – 3.49; P=0.02). Unadjusted OR for patient subgroups are listed in Table 2. Overall, the effect size was consistent across all subgroups. Key factors are highlighted in Figure 1. Significantly higher rates of clinical success were found for treatment with C/T compared to CZA for patients with pneumonia, SOFA ≤7, mechanical ventilation, and optimal dosing. Table 3 displays comparative 30-day mortality rates. Higher mortality rates were identified in both C/T- and CZA-treated patients who were critically-ill, received suboptimal dosing, and were treated within 72 hours of index culture (Table 3); rates did not vary by treatment. Conclusion The consistency of the results in this subgroup analysis of CACTUS reinforces the primary finding of higher rates of clinical success for patients with MDR P. aeruginosa pneumonia or bacteremia treated with C/T compared to CZA. Disclosures jason M. Pogue, PharmD, Entasis: Advisor/Consultant|GSK: Advisor/Consultant|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Venatorx: Advisor/Consultant Samuel L. Aitken, PharmD, MPH, Basilea: Advisor/Consultant|bioMerieux: Advisor/Consultant|Melinta: Advisor/Consultant|Shionogi: Advisor/Consultant Ahmed Babiker, MBBS, Beckman Coulter Inc.: Advisor/Consultant Kimberly C. Claeys, PharmD, PhD, bioMérieux: Advisor/Consultant|bioMérieux: Honoraria Kate DeSear, PharmD, BCIDP, AAHIVP, FIDSA, AbbVie Inc: Advisor/Consultant|Basilea Pharmaceutica: Advisor/Consultant|GSK: Advisor/Consultant|La Jolla (Entasis): Advisor/Consultant|Melinta Therapuetics: Advisor/Consultant Alan E. Gross, PharmD, Becton Dickinson Co: Advisor/Consultant Keith S. Kaye, MD, MPH, Allecra: Advisor/Consultant|CARB-X: Advisor/Consultant|GSK: Advisor/Consultant|Merck: Advisor/Consultant|Shionogi: Advisor/Consultant|Spero: Advisor/Consultant Wesley D. Kufel, Pharm.D., BCPS, BCIDP, Merck & Co.: Grant/Research Support|Shionogi, Inc: Grant/Research Support Conan MacDougall, PharmD, MAS, Merck: Grant/Research Support Erin K. McCreary, PharmD, Abbvie: Advisor/Consultant|Basilea: Advisor/Consultant|Ciadara: Advisor/Consultant|Entasis: Advisor/Consultant|Ferring: Advisor/Consultant|GSK: Advisor/Consultant|GSK: Honoraria|Melinta: Advisor/Consultant|Merck: Advisor/Consultant|Pfizer: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Honoraria William R. Miller, M.D., Merck: Grant/Research Support|UptoDate: Royalties Jeffrey C. Pearson, PharmD, inflarx: 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 David van Duin, MD, PhD, Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Qpex: Advisor/Consultant|Roche: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support 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

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

Background:Trypanosoma cruzi is a protozoan parasite and the causative agent of Chagas disease. This case describes a fulminant and fatal reactivation of T. cruzi after immunosuppression in a patient with a history of follicular lymphoma, with parasitemia detectable in peripheral blood smears and parasites seen in multiple autopsy tissue specimens. Case Summary:A 61-year-old woman who had immigrated from El Salvador and was receiving obinutuzumab and zanubrutinib for follicular lymphoma in remission was admitted with persistent COVID-19 pneumonia. After multiple therapies for COVID-19, including more than 3 weeks of corticosteroid therapy for the possibility of organizing pneumonia, a peripheral blood smear identified T. cruzi trypomastigotes, and later amastigotes were identified in a bone marrow biopsy. The patient was treated with benznidazole but ultimately died. At autopsy, amastigotes were observed in multiple organs, including the heart, esophagus, stomach, small intestine, colon, bladder, and skeletal muscle. Conclusion:Most cases of Chagas reactivation are described in people living with HIV-1 or transplant recipients. Rarely, T. cruzi reactivation can occur in patients undergoing immunosuppressive therapies for malignancies or inflammatory states like COVID-19 infection, as seen in this case. If not recognized early, reactivation can be fatal despite antiparasitic treatment. Providers should consider screening patients from endemic areas who will start on immunosuppressive therapies. Repeating screening may be of value with periods of new immunosuppression. In patients with Chagas disease and malignancy, PCR from blood should be performed during enhanced immunosuppression so that preemptive treatment can be initiated prior to the presentation of fulminant disease.

BACKGROUND:Infections are the second leading cause of death in patients with cancer and are often caused by resistant bacteria. However, the frequency of antimicrobial resistance (AMR) in outpatients with cancer is not well understood. We aimed to compare the frequency of AMR bacterial pathogens in outpatients with and without cancer. METHODS:This retrospective cohort study evaluated antimicrobial susceptibility of bacteria isolated from adults (aged ≥18 years) with and without cancer seeking care in 198 outpatient health-care settings in the USA. Data were collected using the BD Insights Research Database. Patients who were not prescribed cancer medications or not admitted to an inpatient cancer unit in the predefined period were categorised as patients without cancer. Patients were included in the cancer cohort if they received medication solely or sometimes indicated for cancer. Data on gender and race or ethnicity were not collected. Non-duplicate and non-contaminant pathogens collected from various samples (ie, blood, intra-abdominal, respiratory, urine, skin or wound, and other) in outpatients were used to assess the coprimary outcomes: overall and source-specific proportions of non-susceptible pathogen isolates with corresponding AMR odds ratios (ORs); and rates of AMR pathogens per 1000 isolates with corresponding AMR incidence rate ratio (IRR) in patients with and without cancer. FINDINGS:Data were collected between April 1, 2018, and Dec 31, 2022. 53 006 (3·2%) of 1 655 594 pathogens identified were from 27 421 patients with cancer and 1 602 588 (96·8%) were from 928 128 patients without cancer. For Pseudomonas aeruginosa, carbapenem non-susceptibility was higher in pathogen isolates from patients with cancer (816 [14·4%] of 5683) than patients without cancer (10 709 [11·3%] 94 419; OR 1·22 [95% CI 1·13-1·32]). For Enterobacterales, fluoroquinolone non-susceptibility was higher in pathogen isolates from patients with cancer (8662 [28·0%] of 30 867) than patients without cancer (238 479 [21·8%] of 1 095 996; OR 1·44 [1·40-1·47]), as was carbapenem non-susceptibility (472 [1·5%] of 30 867 vs 9165 [0·8%] of 1 095 996; OR 1·89 [1·72-2·07]), multidrug-resistant pathogens (2672 [8·7%] of 30 867 vs 48 962 [4·5%] of 1 095 996; OR 2·03 [1·95-2·11]), and extended-spectrum β-lactamase producers (4343 [16·5%] of 26 327 vs 93 977 [9·4%] of 996 853; OR 1·96 [1·90-2·03]). For Staphylococcus aureus, meticillin resistance was higher in pathogen isolates from patients with cancer (4747 [53·0%] of 8959) than patients without cancer (129 291 [48·3%] of 267 520; OR 1·20 [1·15-1·25]). For Enterococcus spp, vancomycin resistance was higher in pathogen isolates from patients with cancer (1329 [18·6%] of 7145) than patients without cancer (12 333 [9·1%] of 135 772]; ORR 2·20 [2·06-2·34). The rates and corresponding IRRs of AMR pathogens per 1000 isolates was also higher in patients with cancer compared with patients without cancer, particularly for carbapenem non-susceptible P aeruginosa (IRR 2·06 [1·91-2·21]) and vancomycin-resistant enterococci (IRR 3·06 [2·89-3·24]). For all comparisons, p<0·0001. INTERPRETATION:AMR proportions and IRRs for most key pathogens were up to three-times higher in isolates from outpatients with cancer than those without cancer, highlighting the need for enhanced surveillance, infection prevention, and timely diagnostic stewardship to improve antibiotic prescribing in this population. FUNDING:AMR Action Fund.

Abstract Background Infections with carbapenem-resistant (CR) organisms are more likely in patients with comorbidities and are associated with worse prognosis. The effect of specific and multiple comorbidities on the outcomes of patients with CR infections is not known. Age-adjusted Charlson Comorbidity Index calculation. The Charlson Comorbidity Index (CCI) scores for patients were calculated according to weights for respective comorbid conditions, as defined by the original CCI scoring system. Age adjustment was consecutively done to obtain the final age-adjusted CCI score. Methods A secondary analysis was conducted on patients enrolled into MDRO Network studies (CRACKLE-2, SNAP, POP), between December 2018 and November 2019, who had blood and respiratory infections with CR Enterobacterales (CRE), Acinetobacter baumannii (CRAb), or Pseudomonas aeruginosa (CRPa). Respiratory cultures were physician-adjudicated. Patients were stratified into 4 groups according to their age-adjusted Charlson Comorbidity Index (CCI) score: 0-2, 3-4, 5-6, and 7+ (Figure 1). Primary outcome was 30-day all-cause mortality; absolute mortality differences comparing presence and absence of comorbidities and 95% score confidence intervals were calculated. Age-adjusted Charlson Comorbidity Index and 30-day mortality. 30-day mortality for patients with carbapenem-resistant Gram-negative bloodstream and respiratory infections increases progressively with increasing age-adjusted Charlson Comorbidity Index score groups. Results 2468 patients were included, of which 66% had CRE, 17% had CRAb, and 17% had CRPa. We found a progressive increase in 30-day mortality rates with rising age-adjusted CCI scores (p < 0.001, Mantel Haenszel Chi-square); 18% (CCI 0-2) to 25% (3-4), further to 28% (5-6), and peak at 35% (7+) (Figure 2). Patients with lower CCI acquired infections later during hospitalization [Median (IQR) days (CCI 0-2: 11 (2, 24.5); 3-4: 10 (2, 26); 5-6: 8 (1, 24); 7+: 9 (1, 25) (Kruskal Wallis p=0.025)], and tended to have a longer length of stay [Median (IQR) days (CCI 0-2: 32 (16, 60); 3-4: 29 (15, 48); 5-6: 25 (13, 50); 7+: 24 (13, 47) (Kruskal Wallis p < 0.001)]. Diabetes was associated with higher 30-day mortality: 23% in non-diabetics, 27% in diabetics without end-organ damage, and 38% in diabetics with end-organ damage (p < 0.001). Diseases with the highest mortality difference when present were cirrhosis with portal hypertension (14.9% [3.2%, 27.8%] 95% CI, p=0.01), diabetes with end-organ damage (14.7% [8.2%, 21.6%], p< 0.001), and lymphoma (12.1% [0%, 25.9%], p=0.05) (Table 1). 30-day mortality differences of Charlson Score components among blood and respiratory infections. 30-day mortality for individual comorbid conditions in the Charlson Comorbidity Index (CCI) is observed using unadjusted risk difference. Each component was compared to patients without each respective comorbidity. The highest risk differences are observed in diabetes with end-organ damage, chronic kidney disease, lymphoma, and cirrhosis with portal hypertension. Conclusion Increasing comorbidities as measured by age-adjusted CCI are associated with worse outcomes in the setting of CR Gram-negative bacterial blood and respiratory infections. Diabetes contributes to this association to a great extent. This may help identify patients at-risk for poor outcomes. Disclosures Yohei Doi, MD, PHD, AbbVie: Honoraria|Entasis: Grant/Research Support|Gilead: Advisor/Consultant|GSK: Advisor/Consultant|Meiji Seika: Advisor/Consultant|Moderna: Advisor/Consultant|Pfizer: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Honoraria David Paterson, bioMerieux: Grant/Research Support|bioMerieux: Honoraria|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Pfizer: Honoraria|Shionogi: Grant/Research Support|Shionogi: Honoraria Michael J. Satlin, MD, AbbVie: DSMB participant|bioMerieux: Grant/Research Support|Merck: Grant/Research Support|Selux Diagnostics: Grant/Research Support|SNIPRBiome: Grant/Research Support Vance G. Fowler, MD, MHS, Affinergy: Advisor/Consultant|ArcBio: Stocks/Bonds (Private Company)|Armata: Advisor/Consultant|Astra Zeneca: Advisor/Consultant|Astra Zeneca: Grant/Research Support|Basilea: Advisor/Consultant|Basilea: Grant/Research Support|ContraFect: Advisor/Consultant|ContraFect: Grant/Research Support|Debiopharm: Advisor/Consultant|Destiny: Advisor/Consultant|EDE: Grant/Research Support|Genentech: Advisor/Consultant|Genentech: Grant/Research Support|GSK: Advisor/Consultant|Janssen: Advisor/Consultant|Karius: Grant/Research Support|MedImmune: Grant/Research Support|Merck: Grant/Research Support|sepsis diagnostics: Patent pending|UptoDate: Royalties|Valanbuio: Stocks/Bonds (Private Company)|Valanbuio: Stocks/Bonds (Private Company) David van Duin, MD, PhD, Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Qpex: Advisor/Consultant|Roche: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support

Background and objectives:The β-lactam/β-lactamase inhibitor combinations ampicillin-sulbactam (SAM) and amoxicillin-clavulanate (AMC) are frequently used to treat Enterobacterales infections and are often assumed to be interchangeable, leading some clinical microbiology laboratories to report antimicrobial susceptibility testing (AST) results for only one of these agents. Given differences in β-lactamase inhibition between sulbactam and clavulanate, we hypothesized that the in vitro activities of SAM and AMC may differ. Methods:To understand the prevalence of discordant SAM and AMC susceptibility results in Enterobacterales species, we analysed AST results obtained by broth microdilution (MicroScan WalkAway, Beckman Coulter) for Enterobacterales isolates recovered from clinical specimens between 2018 and 2022 at an academic medical centre in New York City. Results:Percentages of isolates susceptible to SAM were lower than percentages susceptible to AMC for Escherichia coli (58.1% versus 85.4% of 23,746 isolates, P < 0.0001), Klebsiella pneumoniae group (76.7% versus 88.7% of 6,630, P < 0.0001), Proteus mirabilis (88.0% versus 95.4% of 3,185, P < 0.0001) and Klebsiella oxytoca (69.6% versus 90.7% of 890, P < 0.0001). Isolates of E. coli, K. pneumoniae group and P. mirabilis with susceptibility profiles consistent with ESBL production (ceftriaxone resistant and cefoxitin susceptible) were more likely to be susceptible to AMC but not susceptible to SAM than isolates without this susceptibility phenotype (E. coli, 38% versus 27%, P < 0.0001; K. pneumoniae group: 40% versus 10%, P < 0.0001; P. mirabilis: 24% versus 6%, P < 0.0001). Conclusions:The high prevalence of SAM-not susceptible, AMC-susceptible isolates supports reporting AST results for both SAM and AMC to maximize options for antimicrobial therapy and to support antimicrobial stewardship.

Abstract Background Recently, comparative phylogenetics dictated the formerly named Enterobacter aerogenes be separated from the genus Enterobacter and renamed Klebsiella aerogenes (KA); however, it remains unclear whether the genotypic differences responsible for the reclassification translate into clinical differences. We aimed to evaluate clinical characteristics and outcomes of patients colonized or infected with carbapenem-resistant (CR) Enterobacter cloacae complex (ECC) or CR KA. Methods We conducted a nested, case-control study of patients hospitalized from May 9th, 2016 until November 11th, 2019 and enrolled in The Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacterales II (CRACKLE-2). Cases were patients with an index culture with CR KA and controls were patients with an index culture positive for CR ECC, matched to each case by: 1) country, 2) anatomical source, 3) infection vs. colonization, and 4) availability/result of whole genome sequencing for the isolate. Where WGS was available the pan-genome Ortholog Clustering Tool was used to identify flexible genomic islands (FGI) associated with KA (n=65) versus ECC (n=66). Results Cases with CR KA (n=95) were matched with 95 controls with CR ECC. 49% of cultures met infection criteria. When compared with control patients, cases with KA were less likely to have liver disease (6% vs. 19%,p=0.009) but more likely to have been admitted for longer at the time of culture (median [IQR] 16[1,32] vs. 7[1,23]), have a Pitt score ≥ 4 (53% vs. 38%, p=0.041), and to have been in an intensive care unit (ICU) at the time of culture (54% vs. 45%, p=0.246) (Table 1). 30-day mortality (21% vs. 25%, p=0.492), 90-day mortality (26% vs. 35% p=0.208), and 30-day DOOR outcomes (p=0.727) did not differ between cases and controls for all patients (Figure 1, 2). There were 94 unique FGI containing 216 putative virulence factors for KA versus 77 and132 for ECC. Conclusion Despite significant differences in baseline characteristics and in the putative virulence genes present, clinical outcomes are similar in patients with CR KA and CR ECC colonization and infection (alive without events 37% vs. 36%). Disclosures Michael J. Satlin, MD, AbbVie: DSMB participant|bioMerieux: Grant/Research Support|Merck: Grant/Research Support|Selux Diagnostics: Grant/Research Support|SNIPRBiome: Grant/Research Support Keith S. Kaye, MD, MPH, Allecra: Advisor/Consultant|CARB-X: Advisor/Consultant|GSK: Advisor/Consultant|Merck: Advisor/Consultant|Shionogi: Advisor/Consultant|Spero: Advisor/Consultant Carol Hill, PhD, Glaxo SmithKline: Retirement Health, Cash Balance Plan|Glaxo SmithKline: Stocks/Bonds (Public Company) David van Duin, MD, PhD, Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Qpex: Advisor/Consultant|Roche: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support

Antimicrobial resistance (AMR) disproportionately affects people who are immunocompromised due to their frequent encounters with the health-care system and repeated, prolonged exposure to antibiotics. AMR threatens to undermine continued advances in cancer care, haematopoietic cell transplantation, and solid organ transplantation by severely restricting therapeutic options. The convergence of several factors in the diagnostic evaluation of infection among individuals with immunocompromising conditions contributes to excess and inappropriate antibiotic use. Diagnostic and antimicrobial stewardship are key complementary strategies to address these challenges with shared goals of improving patient outcomes, reducing harm, and mitigating the risk of AMR. In this Series paper, we discuss opportunities to enhance use of existing diagnostic tools (eg, culture-based diagnostics, molecular diagnostics, and other tools such as antibiotic allergy delabelling), emerging diagnostic tools (eg, metagenomic sequencing and host response profiling), and digital innovation, to optimise antibiotic use, and the potential for precision medicine approaches to combat AMR in people who are immunocompromised.

Abstract Background Ceftolozane-tazobactam (CT) and ceftazidime-avibactam (CZA) are front-line agents for treatment of multidrug-resistant (MDR) Pseudomonas aeruginosa; however, real-world comparative-effectiveness data are lacking. Methods CACTUS is a retrospective, matched, multicenter study to compare the efficacy of CT and CZA among patients with bacteremia or pneumonia due to MDR P. aeruginosa. CT and CZA patients were matched 1:1 within each study site by the presence/absence of septic shock/severe sepsis, infection site, and time to treatment initiation. The primary outcome was clinical success at day 30 defined as survival, resolution of signs/symptoms with the intended treatment course, and absence of recurrent infections. Patients with cystic fibrosis or COVID-19 infection within 90 days were excluded. Results 234 patients were included from 20 sites. Patient demographics, severity of illness, infection types, and treatment durations were similar for patients treated with CT or CZA (Table 1). The overall median age was 61 years, 61% were male, and the median Charlson score was 5. At study drug initiation, 77% of patients were in the ICU, 67% received mechanical ventilation and the median SOFA score was 7. 79% of patients were treated for pneumonia; 72% of which occurred in ventilated patients. The median time from index culture to treatment initiation was 72 hours in both groups; CT patients were more likely to receive a prolonged infusion of ≥3 hours (36% vs 19%; P=0.005). Clinical success occurred in 62% and 55% of patients receiving CT and CZA, respectively (P=0.35; Table 1). Corresponding rates of success for pneumonia were 63% and 52%, respectively (P=0.13; Figure 1). All-cause, 30-day mortality rate was 20% and 19%, respectively. Microbiologic failures, recurrent infections, and development of resistance within 90 days were similar between groups. Time to a composite endpoint of recurrent infection or death within 90 days was similar between groups in the overall analysis and the subgroup of patients with pneumonia (Figure 2). Conclusion In this interim analysis of the CACTUS study, patients treated with CT and CZA had similar clinical outcomes. We plan to continue enrollment up to 420 patients to detect if any differences exist in the efficacy of CT and CZA for MDR P. aeruginosa infections. 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 Lilian M. Abbo, MD, MBA, Ferring: Advisor/Consultant|Pfizer: Advisor/Consultant|Regeneron: Grant/Research Support|Shionogi: Advisor/Consultant Ahmed Babiker, MBBS, Roche: Advisor/Consultant Kimberly C. Claeys, PharmD, Abbvie: Advisor/Consultant|bioMérieux Inc.: Advisor/Consultant|bioMérieux Inc.: Speaker|La Jolla Pharmaceuticals: Advisor/Consultant|Melinta Therapeutics: Advisor/Consultant Jason C. Gallagher, PharmD, Entasis: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Qpex: Advisor/Consultant|Shionogi: Advisor/Consultant|Spero: Advisor/Consultant Emily L. Heil, PharmD, MS, Wolters Kluwer-LexiComp: Advisor/Consultant Wesley D. Kufel, PharmD, BCPS, BCIDP, AAHIVP, Merck and Co: Grant/Research Support Amy Mathers, MD, D(ABMM), Merck: Advisor/Consultant Erin K. McCreary, PharmD, Abbvie: Advisor/Consultant|Ferring: Advisor/Consultant|GSK: Honoraria|La Jolla (Entasis): Advisor/Consultant|LabSimply: Advisor/Consultant|Merck: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Honoraria Christopher Polk, MD, ViiVHealthcare: Job change to work for ViiV as Medical Director Michael J. Satlin, MD, AbbVie: IDMC member|Biomerieux: Grant/Research Support|Merck: Grant/Research Support|SNIPRBiome: Grant/Research Support Michael Veve, PharmD, MPH, National Institutes of Health: Grant/Research Support|Paratek Pharmaceuticals: Grant/Research Support 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

Background: Infections are a leading cause of death in patients with cancer, but the proportion and rate of antimicrobial resistance (AMR) in hospitalized patients with cancer are not well understood. Methods: This retrospective, cross-sectional evaluation of AMR assessed hospitalized adult patients in 168 United States (US) healthcare facilities between April 2018 and December 2022. Nonduplicate, noncontaminant Gram-negative and Gram-positive bacteria recovered from various samples (blood, respiratory, urine, etc.) were used to assess the rate of AMR pathogens per 1000 admissions and the proportion of AMR among bacterial isolates in patients with and without cancer. Findings: Among 4,612,620 admissions, 6.4% (297,500) were of patients with cancer and 93.6% (4,315,120) were of patients without cancer. AMR pathogen rates were higher in cancer patients than patients without cancer for most pathogen groups, including vancomycin-resistant enterococci with incidence rate ratio (IRR), 1.95 (95% confidence interval [CI], 1.84, 2.07), extended-spectrum beta-lactamase (ESBL) producers (IRR, 1.48 [95% CI, 1.43, 1.53]), carbapenem-nonsusceptible Enterobacterales (IRR, 1.46 [95% CI, 1.32, 1.61]), and multidrug-resistant Pseudomonas aeruginosa (IRR, 1.31 [95% CI, 1.18, 1.45]). The percentage of nonsusceptible isolates in most pathogen groups was lower in patients with versus without cancer except for ESBL producers among Enterobacterales (odds ratio (OR), 1.11 [95% CI, 1.07, 1.15]) and vancomycin resistance among enterococci (OR, 1.22 [95% CI, 1.14, 1.30]), which were higher in cancer patients. Conclusion: AMR rates for certain key pathogens were 1.5-2 times greater in hospitalized cancer patients compared to hospitalized noncancer patients. The increased AMR rate in cancer patients highlights the need for enhanced infection prevention and diagnostic stewardship efforts.

Background:Multidrug resistant Pseudomonas aeruginosa (PA) represents a serious threat to hospitalized patients. Characterizing the incidence of PA infection and degree of resistance can inform empiric treatment and preventative measures.Objectives:We sought to describe trends in incidence and resistance characteristics of PA bloodstream infections (BSI) observed within the Veterans Health Administration (VHA) system and identify factors contributing to higher observed mortality within this population.Methods:We characterized demographic and clinical features of unique patients among the VHA population presenting with their first episode of PA-BSI between 2009 and 2022 and summarized trends related to mortality and resistance phenotype based on year and geographical location. We additionally used logistic regression analysis to identify predictors of 30-day mortality among this cohort.Results:We identified 8039 PA-BSIs during the study period, 32.7% of which were hospital onset. Annual PA-BSI cases decreased by 35.8%, and resistance among all antimicrobial classes decreased during the study period, while the proportion of patients receiving early active treatment based on susceptibility testing results increased. Average 30-day mortality rate was 23.3%. Higher Charlson Comorbidity Index, higher mAPACHE score, VHA facility complexity 1b and hospital-onset cases were associated with higher mortality, and early active treatment was associated with lower mortality.Conclusions:PA-BSI resistance decreased across the VHA system during the study period. Further investigation of antimicrobial stewardship measures possibly contributing to the observed decreased resistance in this cohort and identification of measures to improve on the high mortality associated with PA-BSI in the VHA population is warranted.

BACKGROUND:The Infectious Diseases Society of America (IDSA) is committed to providing up-to-date guidance on the treatment of antimicrobial-resistant (AMR) infections. This guidance document focuses on infections caused by extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E), AmpC β- lactamase-producing Enterobacterales (AmpC-E), carbapenem-resistant Enterobacterales (CRE), Pseudomonas aeruginosa with difficult-to-treat resistance (DTR P. aeruginosa), carbapenem-resistant Acinetobacter baumannii (CRAB), and Stenotrophomonas maltophilia. This updated document replaces previous versions of the guidance document. METHODS:A panel of six infectious diseases specialists with expertise in managing antimicrobial- resistant infections formulated questions about the treatment of infections caused by ESBL-E, AmpC-E, CRE, DTR P. aeruginosa, CRAB, and S. maltophilia. Because of differences in the epidemiology of AMR and availability of specific anti-infectives internationally, this document focuses on the treatment of AMR infections in the United States. RESULTS:Preferred and alternative suggested treatment approaches are provided with accompanying rationales, assuming the causative organism has been identified and antibiotic susceptibility results are known. Approaches to empiric treatment, transitioning to oral therapy, duration of therapy, and other management considerations are discussed briefly. Suggested approaches apply for both adult and pediatric populations, although suggested antibiotic dosages are provided only for adults. CONCLUSIONS:The field of AMR is highly dynamic. Consultation with an infectious diseases specialist is recommended for the treatment of AMR infections. This document is current as of December 31, 2023 and will be updated periodically. The most current version of this document, including date of publication, is available at www.idsociety.org/practice-guideline/amr-guidance/.