IHMA, Inc. In Vitro Activities of Aztreonam-avibactam and Ceftazidime-avibactam Against Less Commonly Encountered Gram-Negative 2122 Palmer Drive P1155 Schaumburg, IL 60173 USA Bacteria Collected During the ATLAS Global Surveillance Program 2012-2017 www.ihma.com M. Hackel1, G Stone2, B. deJonge3, D. Sahm1 1IHMA, Inc., Schaumburg IL, USA 2Pfizer Inc., Cambridge, MA USA 3Pfizer Inc., Cambridge MA, USA Introduction Results Results While antimicrobial susceptibility Table 1. Less commonly isolated gram-negative species Table 2. In vitro activity of ceftazidime-avibactam, aztreonam-avibactam and comparators against less commonly encountered gram-negative bacteria collected in 2012-2017 . ATM-AVI and CAZ-AVI showed MIC90 values from the ATLAS Global Surveillance Program 2012-2017 AZT-AVI CAZ-AVI CST* MEM TGC TZP LVX profiles have been well described in Organism N ranging from ≤0.015 to 0.5 mg/L and 0.06 to 1 %S MIC Range %S MIC Range %S MIC Range %S MIC Range %S MIC Range %S MIC Range %S MIC Range more common members of the 90 90 90 90 90 90 90 mg/L, respectively, against members of the Organism N Percent of total Acinetobacter nosocomialis 183 na 64 2 - >128 na 32 1 - >128 96.8 2 0.25 - >8 79.8 > 8 0.015 - >8 na 1 0.06 - 4 na > 128 ≤0.25 - >128 76.5 >4 0.06 - >8 Enterobacterales, notably Escherichia Enterobacterales (Table 2). 98.3% were coli and Klebsiella pneumoniae, and in Acinetobacter nosocomialis 183 5.1 Acinetobacter pittii 402 na 64 2 - >128 na 16 0.5 - >128 99.2 2 0.12 - 4 92.3 1 ≤0.06 - >8 na 1 0.03 - >8 na 64 ≤0.25 - >128 88.6 2 0.06 - >8 Citrobacter spp. 400 na 0.25 ≤0.015 - 4 98.8 0.5 ≤0.015 - >128 100 1 ≤0.06 - 2 98.8 0.06 0.008 - >8 99.3 0.5 0.03 - 2 82.8 32 ≤0.25 - >128 89.0 1 ≤0.03 - >8 susceptible to CAZ-AVI (Figure 2), and 100% had Pseudomonas aeruginosa, the Acinetobacter pittii 402 11.2 Enterobacter asburiae 584 na 0.5 ≤0.015 - 8 98.8 0.5 ≤0.015 - >128 47.2 > 8 ≤0.06 - >8 98.1 0.25 0.015 - >8 95.4 1 ≤0.015 - 4 78.9 64 ≤0.25 - >128 90.9 0.5 0.015 - >8 AZT-AVI MIC values ≤8 mg/L (Figure 1). emergence and dissemination of Citrobacter braakii 322 9.0 Enterobacter kobei 193 na 0.5 ≤0.015 - 4 100 0.5 ≤0.015 - 4 89.4 4 ≤0.06 - >8 99.0 0.12 ≤0.004 - >8 96.9 1 0.06 - 4 78.2 64 ≤0.25 - >128 91.2 0.5 ≤0.03 - 8 . CAZ-AVI was active against Pseudomonas spp. resistance is also of concern in less Enterobacter ludwigii 53 na 0.25 ≤0.015 - 1 100 0.5 0.03 - 1 93.6 1 0.12 - >8 100 0.12 0.015 - 0.12 94.3 1 0.12 - 2 86.8 16 ≤0.25 - 128 96.2 0.12 ≤0.03 - 8 (MIC = 8 mg/L), but not against S. maltophilia commonly isolated species. Citrobacter farmeri 43 1.2 Pluralibacter gergoviae 11 na 0.5 ≤0.015 - 0.5 100 1 0.03 - 1 100 0.5 0.25 - 0.5 100 0.06 0.03 - 0.12 100 0.5 0.25 - 0.5 100 8 ≤0.25 - 8 100 0.12 ≤0.03 - 0.12 90 (MIC90 = 128 mg/L) (Table 2, Figure 3). Ceftazidime-avibactam (CAZ-AVI) is a Citrobacter gillenii 2 0.1 Proteus hauseri 211 na ≤0.015 ≤0.015 - 2 100 0.06 ≤0.015 - 1 1.0 > 8 1 - >8 100 0.12 0.03 - 2 86.3 2 0.12 - >8 100 1 ≤0.25 - 4 95.3 0.25 0.015 - >8 newly introduced agent with good Proteus penneri 86 na ≤0.015 ≤0.015 - 0.03 100 0.06 ≤0.015 - 0.12 0 > 8 > 4 - >8 100 0.12 0.03 - 0.25 54.7 4 0.5 - >8 100 0.5 ≤0.25 - 4 89.5 1 ≤0.03 - 4 . ATM-AVI was active against S. maltophilia (MIC90 = Citrobacter murliniae 8 0.2 Providencia alcalifaciens 28 na 0.03 ≤0.015 - 0.5 100 0.5 ≤0.015 - 0.5 0 > 8 > 4 - >8 100 0.25 0.03 - 0.25 28.6 4 0.5 - 8 96.4 8 ≤0.25 - 16 71.4 > 4 0.12 - >8 activity against Enterobacterales 8 mg/L), but not against Pseudomonas spp. (MIC90 Providencia rettgeri 474 na 0.03 ≤0.015 - 16 94.5 0.25 ≤0.015 - >128 1.6 > 8 0.12 - >8 94.7 0.25 0.015 - >8 42.0 4 0.06 - 8 93.3 2 ≤0.25 - >128 72.8 > 4 ≤0.03 - >8 producing class A, C and some class Citrobacter sedlakii 22 0.6 = 64 mg/L) (Table 2, Figure 4). Providencia stuartii 649 na 0.06 ≤0.015 - 4 96.6 0.5 ≤0.015 - >128 0.2 > 8 0.25 - >8 97.8 0.25 ≤0.004 - >8 36.1 4 ≤0.015 - >8 93.1 8 ≤0.25 - >128 30.1 > 8 ≤0.03 - >8 . Colistin was the most active agent against D β-lactamases, but is not active Citrobacter youngae 3 0.1 Pseudomonas spp. 50 na 64 ≤0.015 - >128 92.0 8 0.12 - >128 97.5 2 0.25 - 8 54.0 8 ≤0.06 - >8 0 8 0.12 - >8 76.0 64 0.5 - >128 46.0 > 4 0.06 - >8 against isolates that carry class B Raoultella ornithinolytica 157 na 0.12 ≤0.015 - 16 98.7 0.5 ≤0.015 - >128 100 1 0.12 - 2 98.1 0.06 0.03 - >8 98.1 0.5 0.06 - 4 93.0 8 ≤0.25 - >128 89.2 2 0.008 - 8 Pseudomonas spp. and S. maltophilia (both MIC90 metallo-β-lactamases (MBLs). Enterobacter asburiae 584 16.3 Serratia spp. 37 na 0.12 ≤0.015 - 0.5 100 0.5 0.06 - 1 11.5 > 8 0.5 - >8 100 0.12 0.03 - 0.12 89.2 2 0.12 - 4 97.3 4 0.5 - >128 91.9 0.5 ≤0.03 - 4 of 2 mg/L). Aztreonam-avibactam (ATM-AVI) is a Enterobacter kobei 193 5.4 Stenotrophomonas maltophilia 64 Na 8 1 - 16 na 128 0.5 - >128 na 2 0.12 - 4 na > 8 2 - >8 na 4 0.12 - 8 na > 128 8 - >128 na > 4 0.25 - >8 . Neither CAZ-AVI nor ATM-AVI was very active combination that is under ATM-AVI, aztreonam-avibactam; CAZ-AVI, ceftazidime-avibactam; CST, colistin; MEM, meropenem; TGC, tigecycline; TZP, piperacillin-tazobactam; LVX, levofloxacin; MIC90 and range in mg/L; *colistin not tested in 2012-2013; against Acinetobacter spp. (Table 1) Enterobacter ludwigii 53 1.5 Citrobacter spp. consist of (n): C. braakii (322); C. farmeri (43); C. gillenii (2); C. murliniae (8); C. sedlakii (22); C. youngae (3); Pseudomonas spp. consist of (n): P. alcaliphila (1); P. fluorescens (1); P. mendocina (1); P. monteilii (5); P. mosselii (4); P. nitroreducens (4); development that shows good activity P. otitidis (2); P. putida (28); P. stewartii (1); P. stutzeri (3); Serratia spp. consist of (n): S. odorifera (1); S. rubidaea (2); S. ureilytica (10); S. liquefaciens (24) . Notably, E. asburiae and E. kobei exhibited an Pluralibacter gergoviae 11 0.3 against Enterobacterales producing all MIC90 for colistin in the resistant range. classes of β-lactamases. Proteus hauseri 211 5.9 Figure 1. Aztreonam-avibactam MIC distribution against 2,243 Enterobacterales from 2012-2017 Figure 2. Ceftazidime-avibactam MIC distribution against 2,243 Enterobacterales from 2012- As part of the ATLAS global Proteus penneri 86 2.4 2017 Conclusions surveillance program (2012-2017), this 100 Aztreonam/Avibactam MIC (mg/L) 50 s Providencia alcalifaciens 28 0.8 s study evaluated the in vitro activity of e CAZ-AVI and ATM-AVI showed good activity against e t Serratia spp. (n=37) t a 80 a Serratia spp. (n=37) l l ATM-AVI, CAZ-AVI and comparators o 40 isolates of less commonly encountered gram- Providencia rettgeri 474 13.2 o s s i Citrobacter spp. (n=400) i f Citrobacter spp. (n=400) against clinical isolates of less 60 f negative species, comparable to the activity o o Providencia stuartii 649 18.1 Enterobacter spp. (n=830) 30 e commonly encountered gram-negative e g Enterobacter spp. (n=830) g demonstrated against the more commonly a a t 40 Pseudomonas alcaliphila 1 <0.1 Proteeae (n=976) t species. n 20 n encountered gram-negative pathogens, although e Proteeae (n=976) e c c r Pseudomonas fluorescens 1 <0.1 20 r e e 10 some species-specific antimicrobial susceptibility P P Materials & Methods Pseudomonas mendocina 1 <0.1 patterns may have been identified. 0 0 A total of 109,070 non-duplicate, ≤0.015 0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32 64 > 64 clinically isolated gram-negative Pseudomonas monteilii 5 0.1 ≤0.015 0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32 64 > 64 organisms were collected in 2012- Pseudomonas mosselii 4 0.1 Ceftazidime/Avibactam MIC (mg/L) Dashed line indicates the proposed PK/PD susceptible breakpoint for aztreonam-avibactam Dashed line indicates EUCAST 2019 ceftazidime-avibactam susceptible breakpoint 2017 in the ATLAS program.