200. Antimicrobial Activity of Ceftazidime-Avibactam and Comparators against AmpC Hyperproducing Enterobacterales and P. aeruginosa Collected from United States (US) Medical Centers (2016-2020)
Authors: Sader Helio S , Carvalhaes Cecilia G , Mendes Rodrigo E , Castanheira Mariana , Castanheira Mariana 
Published: December 2021

Abstract

Background
E. cloacae species complex (ECL), S. marcescens (SM), C. freundii species complex (CF), and P. aeruginosa (PSA) are common pathogens in a variety of clinical infections. These organisms can overexpress the chromosomal AmpC that encodes resistance to several β-lactams. We evaluated the activity of ceftazidime-avibactam (CAZ-AVI) and comparators against these organisms.

Methods
17,650 isolates, including 4,400 ECL, 2,074 SM, 1,644 CF, and 9,532 PSA, were consecutively collected from 88 US medical centers in 2016-2020. Among these isolates, 3,127 were ceftazidime-nonsusceptible (CAZ-NS; MIC ≥8 mg/L for Enterobacterales [ENT] and ≥16 mg/L for PSA) and considered probable AmpC hyperproducers. Isolates were susceptibility tested by broth microdilution method.

Results
Susceptibility to CAZ ranged from 73.6% (ECL) to 97.5% (SM; Table). Overall, 99.8% of ENT (99.7-99.9%) and 97.1% of PSA were CAZ-AVI-S; whereas 84.3% (79.0-97.7%) of ENT and 97.4% of PSA were ceftolozane-tazobactam (C-T)-S, 83.0% (78.5-94.8%) of ENT and 80.0% of PSA were piperacillin-tazobactam (PIP-TAZ)-S, and 98.4% (98.3-98.7%) of ENT and 79.5% of PSA were meropenem (MEM)-S. CAZ-AVI retained potent activity and broad spectrum against CAZ-NS ENT (n=1,629; MIC50/90, 0.5/1 mg/L; 99.0%S overall) and CAZ-AVI was more active than MEM (MIC50/90, 0.06/0.5 mg/L; 93.1%S) against these organisms. C-T (MIC50/90, 8/ &gt;16 mg/L; 23.8%S) and PIP-TAZ (MIC50/90, 64/ &gt;64 mg/L; 21.8%S) exhibited limited activity against CAZ-NS ENT. Among comparator agents, only amikacin (99.0%S), tigecycline (95.6%S), and imipenem (92.1%S) showed good activity against CAZ-NS ENT. Also, CAZ-AVI retained activity against 86.7% of ENT isolates that were NS to CAZ and MEM (n=113). CAZ-AVI (MIC50/90, 2/4 mg/L; 97.1%S) and C-T (MIC50/90, 0.5/2 mg/L; 97.4%S) were the most active compounds tested against PSA and both retained activity against CAZ-NS PSA. CAZ-AVI (MIC50/90, 4/16 mg/L; 81.8%S) and C-T (MIC50/90, 2/8 mg/L; 83.9%S) activity against CAZ-NS PSA was comparable to tobramycin (MIC50/90, 1/ &gt;8 mg/L; 82.2%S).

Conclusion
CAZ-AVI demonstrated potent activity and broad spectrum against AmpC hyperproducer organisms, such as ECL, SM, CF, and PSA, from US hospitals and remained highly active against CAZ-NS isolates.

Disclosures
Helio S. Sader, MD, PhD, FIDSA, AbbVie (formerly Allergan) (Research Grant or Support)Basilea Pharmaceutica International, Ltd. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)Department of Health and Human Services (Research Grant or Support, Contract no. HHSO100201600002C)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) Cecilia G. Carvalhaes, MD, PhD, AbbVie (formerly Allergan) (Research Grant or Support)Cidara Therapeutics, Inc. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Pfizer, 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) 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. 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(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