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Background β-lactamase-producing Enterobacterales (Ebact) frequently co-carry resistance to antimicrobials from other classes, limiting treatment options. Avibactam (AVI) inhibits class A, class C, and some class D serine β-lactamases, while aztreonam (ATM) is refractory to hydrolysis by class B metallo-β-lactamases (MBLs). ATM-AVI is being developed for use against drug-resistant isolates of Ebact, especially those co-producing MBLs and serine β-lactamases. This study evaluated the in vitro activity of ATM-AVI and comparators against Ebact collected in 2017-2019 from patients with lower respiratory tract infections (LRTI) as part of the Antimicrobial Testing Leadership and Surveillance (ATLAS) program. Methods Non-duplicate clinical isolates were collected in 52 countries in Europe, Latin America, Asia/Pacific (excluding mainland China and India), and Middle East/Africa. Susceptibility testing was performed by CLSI broth microdilution and interpreted using CLSI 2021 and FDA (tigecycline) breakpoints. ATM-AVI was tested at a fixed concentration of 4 µg/mL AVI. MDR was defined as resistant (R) to ≥3 of 7 sentinel drugs: amikacin, aztreonam, cefepime, colistin, levofloxacin, meropenem, and piperacillin-tazobactam. PCR and sequencing were used to determine the β-lactamase genes present in all isolates with meropenem MIC >1 µg/mL, and Escherichia coli, Klebsiella spp. and Proteus mirabilis with ATM or ceftazidime MIC >1 µg/mL. Results ATM-AVI was active in vitro against Ebact isolates from LRTI (MIC90, 0.25 µg/mL), with 99.97% of isolates inhibited by ≤8 µg/mL of ATM-AVI, including 100% of isolates that produced MBLs. ATM-AVI tested with MIC90 values of 0.5 µg/mL against subsets of cefepime-nonsusceptible (NS), meropenem-NS, amikacin-NS, colistin-resistant, and MBL-positive Ebact (Table). The tested β-lactam comparators showed susceptibility of < 78% against these subsets of resistant isolates. Results Table Conclusion Based on MIC90 values, ATM-AVI was the most potent agent tested against drug-resistant and MBL-positive subsets of Ebact collected from LRTI. The promising in vitro activity of ATM-AVI warrants further development of this combination for treatment of LRTI caused by drug-resistant Ebact. Disclosures Sibylle Lob, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Krystyna Kazmierczak, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Francis Arhin, PhD, Pfizer, Inc. (Employee) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor)

Background Hypervirulent Klebsiella pneumoniae (hvKp), unlike classical K. pneumoniae (cKp), are often responsible for community-acquired infections in otherwise healthy individuals. The acquisition of hypervirulence genes by sequence type 11 (ST11) carbapenem-resistant (CR) Kp endemic in Asia is a grave threat. Aztreonam-avibactam (ATM-AVI) is a monobactam combined with a β-lactamase inhibitor for the treatment of infections caused by Enterobacterales isolates that carry Class A, B, C and some Class D β-lactamases. Methods 487 K. pneumoniae isolates were collected from 17 sites in China in 2019 as a part of the ATLAS global surveillance study. 220 isolates with MICs >1 µg/ml to meropenem (MEM), ceftazidime or ATM were selected for whole genome sequencing (Illumina Hiseq 2x150 bp reads). Analyses were carried out using the CLC Genomics Workbench (Qiagen). Presence of the aerobactin synthesis locus differentiated hvKp and cKp. Antimicrobial susceptibility was determined by CLSI broth microdilution. Results Of the 487 isolates, MIC90 values for ATM-AVI (0.5 µg/ml; Table) were lower than those for any comparator tested, with only two isolates testing with MIC >4 µg/ml. Of the isolates sequenced, 82/220 (37.3%) were ST11. 53/82 (64.6%) of these ST11 isolates were hvKp (ATM-AVI, MIC90 1 µg/ml; range, 0.25-4 µg/ml) and showed percentages of susceptibility < 90% to three last-line agents (0% MEM-susceptible (S); 18.9% amikacin (AMK)-S; 88.7% tigecycline (TGC)-S). Isolates of other STs (Non-ST11) were less frequently identified as hvKp (24/138, 17.4%) and more Non-ST-11 hvKp and cKp alike were S to MEM and AMK relative to isolates of ST11 (75.0-86.8% MEM-S; 83.3-96.5% AMK-S). Likewise, the ATM-AVI MIC90 value (0.25 µg/ml) was 4-fold lower for Non-ST11 isolates. Results Table Conclusion CR ST11 hvKp represented at least 10.9% of the collected Kp isolates. ATM-AVI retained potent in vitro activity against these isolates which displayed resistance to a range of last-line agents. CST and TGC also displayed some activity but are limited in utility due to nephrotoxicity and poor accumulation in blood, respectively. The spread of virulence factors leading to the complicated clinical presentation of hvKp infection into multidrug-resistant lineages warrants continued surveillance. Disclosures Mark Estabrook, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Krystyna Kazmierczak, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Francis Arhin, PhD, Pfizer, Inc. (Employee) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor)