IHMA In Vitro Activities of Ceftazidime-avibactam and Comparator Agents against Enterobacterales and 2122 Palmer Drive 00656 Schaumburg, IL 60173 USA Pseudomonas aeruginosa from Israel Collected Through the ATLAS Global Surveillance Program 2013-2019 www.ihma.com M. Hackel1, M. Wise1, G. Stone2, D. Sahm1 1IHMA, Inc., Schaumburg IL, USA, 2Pfizer Inc., Groton, CT USA Introduction Results Results Summary Avibactam (AVI) is a non-β- Table 1 Distribution of 2,956 Enterobacterales from Israel by species Table 2. In vitro activity of ceftazidime-avibactam and comparators agents Figure 2. Ceftazidime and ceftazidime-avibactam MIC distribution against 29 . Ceftazidime-avibactam exhibited a potent lactam, β-lactamase inhibitor against Enterobacterales and P. aeruginosa from Israel, 2013-2019 non-MBL carbapenem-nonsusceptible (CRE) Enterobacterales from Israel, antimicrobial activity higher than all Organism N % of Total mg/L that can restore the activity of Organism Group (N) %S 2013-2019 comparator agents against all Citrobacter amalonaticus 2 0.1% MIC90 MIC50 Range ceftazidime (CAZ) against Enterobacterales (2956) 20 Enterobacterales from Israel (MIC90, 0.5 Citrobacter braakii 5 0.2% Ceftazidime-avibactam 99.8 0.5 0.12 ≤0.015 - > 128 Ceftazidime Ceftazidime-avibactam organisms that possess Class 18 mg/L; 99.8% susceptible). Citrobacter freundii 96 3.2% Ceftazidime 70.1 64 0.25 ≤0.015 - > 128 A, C, and some Class D β- Cefepime 71.8 > 16 ≤0.12 ≤0.12 - > 16 16 . Susceptibility to ceftazidime-avibactam lactmase enzymes. This study Citrobacter gillenii 1 <0.1% Meropenem 98.8 0.12 ≤0.06 ≤0.06 - > 8 increased to 100% for the Enterobacterales Amikacin 95.4 8 2 ≤0.25 - > 32 14 examined the in vitro activity Citrobacter koseri 123 4.2% when MBL-positive isolates were removed Colistin (n=2544)* 82.2 > 8 0.5 ≤0.06 - > 8 12 of CAZ-AVI and comparators Citrobacter murliniae 1 <0.1% Piperacillin-tazobactam 80.4 32 2 ≤0.12 - > 64 from analysis. against Enterobacterales and Enterobacterales, MBL-negative (2948) N 10 . 100% of MBL-negative, meropenem- Citrobacter sedlakii 4 0.1% Ceftazidime-avibactam 100 0.5 0.12 ≤0.015 - 8 Pseudomonas aeruginosa Ceftazidime 70.3 64 0.25 ≤0.015 - > 128 8 nonsusceptible Enterobacterales isolates Enterobacter asburiae 13 0.4% Cefepime 72.0 > 16 ≤0.12 ≤0.12 - > 16 collected in Israel through the 6 (CRE) were susceptible to ceftazidime- Enterobacter cloacae 211 7.1% Meropenem 99.0 0.12 ≤0.06 ≤0.06 - > 8 ATLAS global surveillance Amikacin 95.5 8 2 ≤0.25 - > 32 avibactam (MIC , 4 mg/L). 4 90 program from 2013 to 2019. Enterobacter cloacae complex 1 <0.1% Colistin (n=2536)* 82.3 > 8 0.5 ≤0.06 - > 8 . Similarly, 100% of KPC-producing Piperacillin-tazobactam 80.5 32 2 ≤0.12 - > 64 2 Enterobacter kobei 4 0.1% CRE, MBL-negative (29) Enterobacterales isolates were susceptible to Ceftazidime-avibactam 100 4 1 0.12 - 8 0 Enterobacter ludwigii 1 <0.1% ceftazidime-avibactam (MIC90, 4 mg/L). Ceftazidime 0 > 128 > 128 16 - > 128 0.12 0.25 0.5 1 2 4 8 16 32 64 > 64 Enterobacter sp. 5 0.2% Cefepime 6.9 > 16 > 16 0.25 - > 16 . Ceftazidime-avibactam also showed greater Meropenem 0 > 8 > 8 4 - > 8 MIC (mg/L) activity than all comparators against P. Escherichia coli 877 29.7% Amikacin 44.8 > 32 16 0.5 - > 32 Dashed line represents the EUCAST 2020 breakpoint of 8 mg/L for ceftazidime-avibactam aeruginosa isolates from Israel (MIC , 4 Klebsiella aerogenes 147 5.0% Colistin (n=23) * 91.3 2 0.5 0.12 - > 8 90 Piperacillin-tazobactam 0 > 64 > 64 32 - > 64 Figure 3. Ceftazidime and ceftazidime-avibactam MIC distribution against 21 mg/L; 98.5% susceptible). Against only the Klebsiella oxytoca 152 5.1% Enterobacterales, KPC-positive (21) Ceftazidime-avibactam 100 4 1 0.12 - 4 KPC-positive Enterobacterales from Israel, 2013-2019 meropenem non-susceptible P. aeruginosa Klebsiella pneumoniae 809 27.4% Ceftazidime 0 > 128 > 128 16 - > 128 16 subset, the activity remained very good as Klebsiella variicola 9 0.3% Cefepime 0 > 16 > 16 0.25 - > 16 Ceftazidime Ceftazidime-avibactam 94.5% of the isolates were susceptible with Methods Meropenem 0 > 8 > 8 4 - > 8 14 Morganella morganii 84 2.8% Amikacin 38.1 > 32 32 0.5 - > 32 only the last resort agent, colistin, exhibiting A total of 2,956 non-duplicate, Colistin (n=16)* 87.5 4 0.5 0.12 - > 8 Pluralibacter gergoviae 1 <0.1% Piperacillin-tazobactam 0 > 64 >64 > 64 - > 64 12 higher activity (96.3% susceptible). clinically isolated Entero- Proteus hauseri 14 0.5% Escherichia coli (877) bacterales and 820 P. Ceftazidime-avibactam 100 0.25 0.12 ≤0.015 - 8 10 Proteus mirabilis 156 5.3% Ceftazidime 72.1 32 0.25 ≤0.015 - > 128 aeruginosa were collected Cefepime 73.9 > 16 ≤0.12 ≤0.12 - > 16 N 8 from five sites in Israel during Proteus penneri 3 0.1% Meropenem 99.7 0.06 0.03 ≤0.06 - > 8 Amikacin 95.4 8 2 0.5 - > 32 Conclusions 2013 to 2019. Susceptibility Proteus vulgaris 68 2.3% 6 Colistin (n=734)* 99.7 1 0.25 ≤0.06 - > 8 Ceftazidime-avibactam demonstrated potent in testing was done using broth Providencia rettgeri 10 0.3% Piperacillin-tazobactam 86.9 16 2 ≤0.25 - > 64 4 Klebsiella pneumoniae (809) vitro activity against Enterobacterales and P. microdilution according to Providencia stuartii 64 2.2% Ceftazidime-avibactam 100 0.5 0.12 ≤0.015 - 8 2 aeruginosa collected in Israel. For infections CLSI guidelines (1) and Raoultella ornithinolytica 3 0.1% Ceftazidime 49.7 128 2 ≤0.015 - > 128 Cefepime 50.6 > 16 1 ≤0.12 - > 16 caused by P. aeruginosa and Enterobacterales interpreted using EUCAST 0 Serratia marcescens 92 3.1% Meropenem 97.4 0.12 ≤0.06 ≤0.06 - > 8 that are MBL-negative, ceftazidime-avibactam 2021 breakpoints (2). CAZ-AVI Amikacin 93.2 8 1 0.5 - > 32 0.12 0.25 0.5 1 2 4 8 16 32 64 > 64 Total 2956 100% Colistin (n=706)* 99.2 1 0.5 ≤0.06 - > 8 offers a compelling therapeutic alternative to was tested with a fixed MIC (mg/L) Piperacillin-tazobactam 61.9 > 64 8 0.5 - > 64 other agents like colistin and meropenem. concentration of 4 mg/L AVI. Enterobacter spp. (235) Dashed line represents the EUCAST 2020 breakpoint of 8 mg/L for ceftazidime-avibactam Organisms non-susceptible to Figure 1. Ceftazidime and ceftazidime-avibactam MIC distribution against Ceftazidime-avibactam 98.7 1 0.25 ≤0.015 - 64 2,956 Enterobacterales from Israel, 2013-2019 Ceftazidime 66.0 128 0.5 0.06 - > 128 Figure 4. Ceftazidime and ceftazidime-avibactam MIC distribution against 820 meropenem were screened Cefepime 74.0 16 ≤0.12 ≤0.12 - > 16 for acquired beta-lactamases 1200 Meropenem 97.5 0.12 ≤0.06 ≤0.06 - > 8 P. aeruginosa from Israel, 2013-2019 Amikacin 98.7 4 1 0.5 - > 32 by PCR, followed by Sanger Ceftazidime Ceftazidime-avibactam 450 Colistin (n=210)* 93.3 1 0.5 ≤0.06 - > 8 Ceftazidime Ceftazidime-avibactam sequencing (3). 1000 Piperacillin-tazobactam 71.1 > 64 2 ≤0.25 - > 64 400 References Pseudomonas aeruginosa (820) 1. CLSI. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow aerobically. 11th ed. CLSI standard M07. Wayne, PA: Clinical 800 Ceftazidime-avibactam 98.5 4 2 ≤0.015 - 32 350 Ceftazidime** 83.8 32 2 0.12 - > 128 and Laboratory Standards Institute; 2018. 2. The European Committee on Antimicrobial Susceptibility Testing. Cefepime** 86.0 16 2 ≤0.12 - > 32 300 Breakpoint tables for interpretation of MICs and zone diameters. Version Meropenem 82.2 8 0.5 0.015 - > 8 600 11.0, 2021. http://www.eucast.org. N Amikacin 97.4 8 4 ≤0.25 - > 64 250 N 3. Lob SH, Kazmierczak KM, Badal RE, Hackel MA, Bouchillon SK, Colistin (n=760)* 97.9 2 1 0.12 - 4 200 Biedenbach DJ, Sahm, DF. 2015. Trends in susceptibility of Escherichia coli 400 Piperacillin-tazobactam** 78.5 > 128 8 ≤0.12 - > 128 from intra-abdominal infections to ertapenem and comparators in the United Pseudomonas aeruginosa, MEM-NS (146) 150 States according to data from the SMART program, 2009 to 2013. Ceftazidime-avibactam 94.5 8 4 1 - 32 Antimicrob Agents Chemother 59:3606-3610. 200 Ceftazidime** 63.0 128 8 1 - > 128 100 Cefepime** 60.3 32 8 1 - > 32 0 Meropenem 0 > 8 8 4 - > 8 50 Amikacin 91.1 16 4 0.5 - > 64 0.015 0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32 64 > 64 Colistin (n=134)* 96.3 2 1 0.25 - 4 0 MIC (mg/L) Piperacillin-tazobactam** 50.7 > 128 16 4 - > 128 0.015 0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32 64 > 64 Disclosures %S, percent susceptible defined using EUCAST 2021 breakpoints; CRE, carbapenem resistant This study was sponsored by Pfizer. IHMA received financial support from Enterobacterales based on meropenem nonsusceptibility (MIC ≥4mg/L); MEM, meropenem; NS, non- MIC (mg/L) Pfizer in connection with the study and the development of this poster. MW, Dashed line represents the EUCAST 2020 breakpoint of 8 mg/L for ceftazidime-avibactam susceptible. MBL, metallo-β-lactamase MH, and DS are employees of IHMA. GS is an employee of Pfizer. *colistin was not tested in 2013 Dashed line represents the EUCAST 2020 breakpoint of 8 mg/L for ceftazidime-avibactam **% “susceptible, increased exposure” is given Presented at ECCMID 2021, July 9-12, 2021 Online.