1218. Activity of Meropenem-Vaborbactam and Comparator Agents Against Carbapenemase-Negative, Carbapenem-Resistant Enterobacterales from US Hospitals

Abstract Background Meropenem-vaborbactam (MVB) is an important addition to the armamentarium to treat infections caused by carbapenem-resistant Enterobacterales (CREs). Carbapenemase-negative (CN) CRE isolates have been reported, but the activity of newer agents against these isolates is still not well understood. We evaluated the activity of MVB against CN-CRE collected during 6 years of surveillance in US hospitals. Methods A total of 27,968 Enterobacterales isolates collected in US hospitals from 2014-2019 were susceptibility tested by reference broth microdilution methods. Results were interpreted using CLSI 2020 breakpoints. CRE isolates were submitted to PCR/sequencing (2014-2015) or whole genome sequencing (WGS; 2016-2019) for characterization of carbapenemase genes. Isolates from 2016-2019 were evaluated for other beta-lactam resistance mechanisms. Results Among 357 (1.3% of all isolates) CRE isolates identified during 6 years of surveillance, 48 (13.4% of the CRE) isolates did not produce known carbapenemases. The CN-CRE collection included 7 bacterial, species, or species complex. The top four most common species in the collection were K. pneumoniae (16 isolates) followed by E. cloacae (9), E. coli (8), and K. aerogenes (8). MVB was the most active agent tested against these isolates, inhibiting 47/48 (97.9%) of the isolates tested. The only isolate displaying a resistant MIC for MVB was a P. mirabilis (MIC, 16 mg/L) collected in 2015. Meropenem alone inhibited only 2.1% of the isolates. Other beta-lactams inhibited 4.2 to 14.6% of the isolates. Among non-beta-lactam comparator agents, tigecycline and amikacin inhibited 93.8 and 91.7% of the isolates, respectively, when applying CLSI or US FDA breakpoints. A total of 89.6% of the isolates had intermediate colistin MIC values. Among the 27 isolates collected from 2016-2019 that were submitted to WGS, 15 harbored CTX-M encoding genes. K. aerogenes and E. cloacae isolates (3 each) overexpressed AmpC. OmpC/K36 was disrupted in 20 isolates and OmpF/K35 was disrupted in 8 isolates. Conclusion MVB displayed good activity against CN-CRE isolates from US hospitals. This combination agent could be a good option to treat infections caused by these isolates. Disclosures Mariana Castanheira, PhD, AbbVie (formerly Allergan) (Research Grant or Support)Bravos Biosciences (Research Grant or Support)Cidara Therapeutics, Inc. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Qpex Biopharma (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Mariana Castanheira, PhD, Affinity Biosensors (Individual(s) Involved: Self): Research Grant or Support; Allergan (Individual(s) Involved: Self): Research Grant or Support; Amicrobe, Inc (Individual(s) Involved: Self): Research Grant or Support; Amplyx Pharma (Individual(s) Involved: Self): Research Grant or Support; Artugen Therapeutics USA, Inc. (Individual(s) Involved: Self): Research Grant or Support; Astellas (Individual(s) Involved: Self): Research Grant or Support; Basilea (Individual(s) Involved: Self): Research Grant or Support; Beth Israel Deaconess Medical Center (Individual(s) Involved: Self): Research Grant or Support; BIDMC (Individual(s) Involved: Self): Research Grant or Support; bioMerieux Inc. (Individual(s) Involved: Self): Research Grant or Support; BioVersys Ag (Individual(s) Involved: Self): Research Grant or Support; Bugworks (Individual(s) Involved: Self): Research Grant or Support; Cidara (Individual(s) Involved: Self): Research Grant or Support; Cipla (Individual(s) Involved: Self): Research Grant or Support; Contrafect (Individual(s) Involved: Self): Research Grant or Support; Cormedix (Individual(s) Involved: Self): Research Grant or Support; Crestone, Inc. (Individual(s) Involved: Self): Research Grant or Support; Curza (Individual(s) Involved: Self): Research Grant or Support; CXC7 (Individual(s) Involved: Self): Research Grant or Support; Entasis (Individual(s) Involved: Self): Research Grant or Support; Fedora Pharmaceutical (Individual(s) Involved: Self): Research Grant or Support; Fimbrion Therapeutics (Individual(s) Involved: Self): Research Grant or Support; Fox Chase (Individual(s) Involved: Self): Research Grant or Support; GlaxoSmithKline (Individual(s) Involved: Self): Research Grant or Support; Guardian Therapeutics (Individual(s) Involved: Self): Research Grant or Support; Hardy Diagnostics (Individual(s) Involved: Self): Research Grant or Support; IHMA (Individual(s) Involved: Self): Research Grant or Support; Janssen Research & Development (Individual(s) Involved: Self): Research Grant or Support; Johnson & Johnson (Individual(s) Involved: Self): Research Grant or Support; Kaleido Biosceinces (Individual(s) Involved: Self): Research Grant or Support; KBP Biosciences (Individual(s) Involved: Self): Research Grant or Support; Luminex (Individual(s) Involved: Self): Research Grant or Support; Matrivax (Individual(s) Involved: Self): Research Grant or Support; Mayo Clinic (Individual(s) Involved: Self): Research Grant or Support; Medpace (Individual(s) Involved: Self): Research Grant or Support; Meiji Seika Pharma Co., Ltd. (Individual(s) Involved: Self): Research Grant or Support; Melinta (Individual(s) Involved: Self): Research Grant or Support; Menarini (Individual(s) Involved: Self): Research Grant or Support; Merck (Individual(s) Involved: Self): Research Grant or Support; Meridian Bioscience Inc. (Individual(s) Involved: Self): Research Grant or Support; Micromyx (Individual(s) Involved: Self): Research Grant or Support; MicuRx (Individual(s) Involved: Self): Research Grant or Support; N8 Medical (Individual(s) Involved: Self): Research Grant or Support; Nabriva (Individual(s) Involved: Self): Research Grant or Support; National Institutes of Health (Individual(s) Involved: Self): Research Grant or Support; National University of Singapore (Individual(s) Involved: Self): Research Grant or Support; North Bristol NHS Trust (Individual(s) Involved: Self): Research Grant or Support; Novome Biotechnologies (Individual(s) Involved: Self): Research Grant or Support; Paratek (Individual(s) Involved: Self): Research Grant or Support; Pfizer (Individual(s) Involved: Self): Research Grant or Support; Prokaryotics Inc. (Individual(s) Involved: Self): Research Grant or Support; QPEX Biopharma (Individual(s) Involved: Self): Research Grant or Support; Rhode Island Hospital (Individual(s) Involved: Self): Research Grant or Support; RIHML (Individual(s) Involved: Self): Research Grant or Support; Roche (Individual(s) Involved: Self): Research Grant or Support; Roivant (Individual(s) Involved: Self): Research Grant or Support; Salvat (Individual(s) Involved: Self): Research Grant or Support; Scynexis (Individual(s) Involved: Self): Research Grant or Support; SeLux Diagnostics (Individual(s) Involved: Self): Research Grant or Support; Shionogi (Individual(s) Involved: Self): Research Grant or Support; Specific Diagnostics (Individual(s) Involved: Self): Research Grant or Support; Spero (Individual(s) Involved: Self): Research Grant or Support; SuperTrans Medical LT (Individual(s) Involved: Self): Research Grant or Support; T2 Biosystems (Individual(s) Involved: Self): Research Grant or Support; The University of Queensland (Individual(s) Involved: Self): Research Grant or Support; Thermo Fisher Scientific (Individual(s) Involved: Self): Research Grant or Support; Tufts Medical Center (Individual(s) Involved: Self): Research Grant or Support; Universite de Sherbrooke (Individual(s) Involved: Self): Research Grant or Support; University of Iowa (Individual(s) Involved: Self): Research Grant or Support; University of Iowa Hospitals and Clinics (Individual(s) Involved: Self): Research Grant or Support; University of Wisconsin (Individual(s) Involved: Self): Research Grant or Support; UNT System College of Pharmacy (Individual(s) Involved: Self): Research Grant or Support; URMC (Individual(s) Involved: Self): Research Grant or Support; UT Southwestern (Individual(s) Involved: Self): Research Grant or Support; VenatoRx (Individual(s) Involved: Self): Research Grant or Support; Viosera Therapeutics (Individual(s) Involved: Self): Research Grant or Support; Wayne State University (Individual(s) Involved: Self): Research Grant or Support Timothy B. Doyle, AbbVie (formerly Allergan) (Research Grant or Support)Bravos Biosciences (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Valerie Kantro, n/a, Melinta Therapeutics, Inc. (Research Grant or Support) Rodrigo E. Mendes, PhD, AbbVie (Research Grant or Support)AbbVie (formerly Allergan) (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)ContraFect Corporation (Research Grant or Support)GlaxoSmithKline, LLC (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Nabriva Therapeutics (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Dee Shortridge, PhD, AbbVie (formerly Allergan) (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Shionogi (Research Grant or Support)

Conclusion. CT, amikacin and IMI/REL showed good activity against RTI isolates and could represent effective treatment options for P. aeruginosa infections. The prevalence of carbapenemases-encoding genes varied geographically in LATAM.
Disclosures. Leandro Cardinal, PharmD, PhD, MSD (Employee) Cicera P. Marcelino, n/a, MSD (Employee) Aline Okuma, n/a, MSD (Employee)MSD Brazil  Meropenem-vaborbactam (MVB) is an important addition to the armamentarium to treat infections caused by carbapenem-resistant Enterobacterales (CREs). Carbapenemase-negative (CN) CRE isolates have been reported, but the activity of newer agents against these isolates is still not well understood. We evaluated the activity of MVB against CN-CRE collected during 6 years of surveillance in US hospitals.
Methods. A total of 27,968 Enterobacterales isolates collected in US hospitals from 2014-2019 were susceptibility tested by reference broth microdilution methods. Results were interpreted using CLSI 2020 breakpoints. CRE isolates were submitted to PCR/sequencing (2014)(2015) or whole genome sequencing (WGS; 2016-2019) for characterization of carbapenemase genes. Isolates from 2016-2019 were evaluated for other beta-lactam resistance mechanisms.
Results. Among 357 (1.3% of all isolates) CRE isolates identified during 6 years of surveillance, 48 (13.4% of the CRE) isolates did not produce known carbapenemases. The CN-CRE collection included 7 bacterial, species, or species complex. The top four most common species in the collection were K. pneumoniae (16 isolates) followed by E. cloacae (9), E. coli (8), and K. aerogenes (8). MVB was the most active agent tested against these isolates, inhibiting 47/48 (97.9%) of the isolates tested. The only isolate displaying a resistant MIC for MVB was a P. mirabilis (MIC, 16 mg/L) collected in 2015. Meropenem alone inhibited only 2.1% of the isolates. Other beta-lactams inhibited 4.2 to 14.6% of the isolates. Among non-beta-lactam comparator agents, tigecycline and amikacin inhibited 93.8 and 91.7% of the isolates, respectively, when applying CLSI or US FDA breakpoints. A total of 89.6% of the isolates had intermediate colistin MIC values. Among the 27 isolates collected from 2016-2019 that were submitted to WGS, 15 harbored CTX-M encoding genes. K. aerogenes and E. cloacae isolates (3 each) overexpressed AmpC. OmpC/K36 was disrupted in 20 isolates and OmpF/K35 was disrupted in 8 isolates.
Conclusion. MVB displayed good activity against CN-CRE isolates from US hospitals. This combination agent could be a good option to treat infections caused by these isolates.

Session: P-72. Resistance Mechanisms
Background. Patients with carbapenem-resistant Pseudomonas aeruginosa (CRPA) have high in-hospital mortality rates. It is unknown if patients with CRPA treated with ceftolozane/tazobactam (C/T) have improved clinical outcomes compared to those treated with polymyxins.
Methods. The CDC-funded, Georgia Emerging Infections Program performed active population-and laboratory-based surveillance for CRPA isolated from sterile sites, urine, lower respiratory tract and wounds in metropolitan Atlanta, GA from 8/1/2016-7/31/2018. We reviewed charts of adults without cystic fibrosis who were hospitalized within 1 week of CRPA culture. Using a desirability of outcome ranking (DOOR) analysis which incorporates both benefits and risks into a single outcome, we estimated the probability that a patient treated first with C/T would have a more desirable clinical outcome at 30-days than a patient treated with polymyxins (polymyxin B or colistin). We adjusted for confounding using inverse probability of treatment weighting (IPTW) based on culture source and need for dialysis at baseline. A partial credit analysis allowed for variable weighting of DOOR ranks and calculation of differences in mean partial credit scores.
Results. Among 710 cases from 18 different hospitals, we identified 73 patients treated for CRPA infections with polymyxins (n=31) or C/T (n=42). Most patients were male (64%) and Black (80%), and those receiving polymyxins were more likely to have required dialysis at baseline (35% vs. 14%, p=0.03) ( Table 1). At 30 days after culture, 34 (47%) were alive with no adverse events, 21 (29%) were alive with ≥ 1 adverse event, and 18 (25%) had died. Patients first treated with C/T had a lower 30-day mortality rate than those treated with polymyxins (14% vs 39%, p=0.03). Additionally, those receiving C/T had better overall clinical outcomes, with an adjusted DOOR probability of having an improved outcome of 67% (95% CI 53%-80%) compared to those receiving polymyxins (Figure 1). Partial credit analyses indicated consistent results across different patient values of survival with adverse events (Figure 2). 1. Percentages are adjusted using inverse probability of treatment weighting, controlling for culture source and need for dialysis at baseline 2. Adverse events measured included: acute kidney injury, discharge to higher acuity location than previous residence, or being hospitalized 30 days after culture