IHMA In Vitro Activities of Ceftazidime-Avibactam and Comparator Agents Against from Europe 2122 Palmer Drive 00651 Schaumburg, IL 60173 USA Stratified by Region, ATLAS Global Surveillance Program 2018-2019 www.ihma.com

M. Estabrook1, K. Kazmierczak1, G. Stone2, D. Sahm1 1IHMA, Inc., Schaumburg IL, USA, 2Pfizer Inc., Groton, CT USA Introduction Results Results Summary Viable options for the effective Table 1 : Distribution of organisms collected for Figure 1A: Ceftazidime-avibactam MIC distribution against isolates collected in Europe, Table 2: In vitro activity of ceftazidime-avibactam and comparator agents against isolates by . Of the 12,283 isolates collected in N/W treatment of infections caused by this study by region phenotype and geography Europe and the 5,574 collected in C/E Enterobacterales continue to diminish Genus (% of Northern/Western Europe (n=12,283) Central/Eastern Europe (n=5,574) Europe, 99.4% and 96.2% were susceptible 40 Drug (MIC [mg/L]/% Susceptible) as multidrug-resistance becomes more total) Species N SR Region/Country/ No. of 90 to ceftazidime-avibactam, respectively (Table Escherichia CAZ-AVI CAZ FEP MEM CST TZP

) 35 prevalent. Ceftazidime-avibactam is a Escherichia coli Phenotype isolates 2; Figure 1A). %

(29%) 5,082 ( MIC %S MIC %S MIC %S MIC %S MIC %S MIC %S

90 90 90 90 90 90

cephalosporin combined with a s 30 . 80.8% (N/W) and 61.8% (C/E) of

Klebsiella e t Northern/Western, all 12,283 0.5 99.4 32 78.0 16 83.6 0.12 97.6 >8 81.0 64 82.0

Klebsiella pneumoniae a diazabicyclooctane β-lactamase (24%) 4,337 l 25 meropenem-non-susceptible (NS) isolates o s i

inhibitor approved in 2016 by the were susceptible to ceftazidime-avibactam cloacae 1,950 f MEM-NS 292 >128 80.8 >128 4.5 >32 2.1 >16 0.0 >8 80.5 >64 1.4 o 20 European Commission for treatment of (Table 2). Activity was increased to 97.5% Enterobacter asburiae e 119 g MEM-NS MBL-NEG 242 a 8 97.5 >128 5.4 >32 2.5 >16 0.0 >8 80.2 >64 1.7 serious Gram-negative bacterial t 15 (N/W) and 98.8% (C/E) susceptible, among

Enterobacter kobei 74 n e b infections requiring hospitalization. c CST-R 198 MBL-negative meropenem-NS isolates (Table Enterobacter cloacae complex r 10 8 93.9 >128 42.9 >32 56.1 >16 75.3 >8 0.0 >64 48.5 73 e

Ceftazidime-avibactam is active Enterobacter P * 2; Figure 1B). Enterobacter ludwigii 45 5 against Enterobacterales isolates that (14%) * * * * * * * Belgium 1,120 0.5 99.6 32 82.1 4 87.2 0.12 99.1 >8 81.2 32 84.7 . Among isolates that were colistin-resistant, Enterobacter xiangfangensis 32 0 produce Class A, C and some Class D Denmark 186 0.5 100 2 89.3 1 93.0 0.12 100 >8 80.7 32 83.9 ceftazidime-avibactam was the most active β-lactamases, but not Class B metallo- Enterobacter bugandensis 24 ≤0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32 64 128 >128 agent tested (93.9% and 87.3% susceptible β-lactamases (MBLs). The in vitro Enterobacter hormaechi 6 MIC (mg/L) Finland 77 0.25 100 1 92.2 0.25 96.1 ≤0.06 100 >8 87.0 4 100 in N/W and C/E Europe, respectively; Table 2; Species undefined activity of ceftazidime-avibactam and 147 *MBLs were identified in 56/69 (81.2%) of isolates collected in Northern/Western-Europe and 202/212 (95.3%) of France 1,838 0.5 99.9 32 80.1 4 86.3 0.12 99.7 >8 79.9 32 84.2 Figure 1C). comparators against Enterobacterales Klebsiella oxytoca 1,009 isolates collected in Central/Eastern-Europe testing with CAZ-AVI MICs ≥16 µg/ml. . In each of the 23 participating countries, Dashed line represents the EUCAST 2021 breakpoint for ceftazidime-avibactam (S, susceptible; R, Resistant). Germany 1,834 0.5 99.7 16 82.1 4 86.8 0.12 99.2 >8 80.4 32 84.6 isolated from different countries in Klebsiella Klebsiella aerogenes 569 percentages of susceptibility to ceftazidime- Europe from 2018-2019 is evaluated (11%) Klebsiella variicola 318 Figure 1B: Ceftazidime-avibactam MIC distribution against meropenem-nonsusceptible Ireland 440 0.5 100 32 78.2 8 84.8 0.12 99.6 >8 85.5 64 82.1 avibactam (92.9%-100% susceptible) were MBL-negative isolates, by region herein. Species undefined 9 Italy 1,674 1 98.2 >128 65.1 >32 69.1 4 89.3 >8 79.9 >64 75.2 comparable to or exceeded susceptibilities to Northern/Western Europe (n=242) Central/Eastern Europe (n=323) all tested comparators, including meropenem Proteus mirabilis 717 40 SR Latvia 197 0.5 100 128 70.1 >32 74.6 0.12 99.5 >8 77.2 32 81.7 Proteus vulgaris and colistin (Table 2). Methods 358 35 ) Lithuania 365 0.5 100 64 64.9 >32 72.1 0.12 99.2 >8 80.6 64 70.7 Proteus Proteus hauseri 57 % ( . 17,857 non-duplicate Entero- (6%) s 30 Proteus penneri 5 e t Netherlands 277 0.25 100 1 91.3 0.25 94.6 ≤0.06 99.6 >8 80.9 8 91.7 Conclusions

bacterales isolates were collected a l 25 Proteus rettgeri 1 o s . Ceftazidime-avibactam demonstrated in vitro from 104 sites in 23 countries in i

Portugal 766 0.5 99.9 64 70.6 32 79.5 0.12 97.8 >8 80.3 >64 75.3 f

Species undefined o 20 Europe from 2018-2019 as part of 2 potency against these isolates collected from e

Serratia marcescens g Spain 2,005 0.5 99.4 32 80.3 4 86.6 0.12 98.2 >8 81.4 64 81.6 the ATLAS global surveillance 941 a patients in Europe as part of the ATLAS

t 15 n

program. Serratia Serratia ureilytica 7 e Sweden 181 0.5 100 16 82.9 8 85.6 ≤0.06 100 >8 85.1 16 89.0 Global Surveillance Program from 2018-2019. c

r 10 . Isolates grouped into Northern/ (5%) Serratia liquefaciens e . MBL-positive Enterobacterales compromised

6 P 5 Switzerland 365 0.5 99.7 16 82.7 4 88.0 0.12 99.5 >8 81.6 16 88.2 Western (N/W) Europe were Serratia fonticola 1 the in vitro activity of many last-in-line agents United Kingdom 958 0.5 98.8 16 82.2 4 88.5 ≤0.06 98.1 >8 83.7 32 84.1 collected from patients in Belgium, Citrobacter freundii 444 0 including ceftazidime-avibactam. ≤0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32 64 128 >128 . Ceftazidime-avibactam is valuable as a Denmark, Finland, France, Citrobacter koseri 361 Central/Eastern, all 5,574 1 96.2 >128 61.1 >32 64.0 2 90.6 >8 81.0 >64 71.0 treatment for infections caused by MBL- Germany, Ireland, Italy, Latvia, Citrobacter braakii MIC (mg/L) 64 MEM-NS 524 >128 61.8 >128 5.9 >32 3.4 >16 0.0 >8 81.1 >64 1.0 Lithuania, the Netherlands, Dashed line represents the EUCAST 2021 breakpoint for ceftazidime-avibactam (S, susceptible; R, Resistant). negative Enterobacterales isolates. Citrobacter amalonaticus 11 Portugal, Spain, Sweden, Citrobacter MEM-NS MBL-NEG 323 Furthermore, it is a viable alternative to Citrobacter farmeri 4 98.8 >128 9.6 >32 5.3 >16 0.0 >8 80.5 >64 1.6 8 Figure 1C: Ceftazidime-avibactam MIC distributions against colistin-resistant isolates, meropenem, which is compromised by Switzerland, and the United (5%) CST-Rb 134 Kingdom. Isolates grouped into Citrobacter gillenii 6 by region >128 87.3 >128 20.2 >32 23.1 >16 45.5 >8 0.0 >64 24.6 carbapenemase production, as well as Citrobacter sedlakii Northern/Western Europe (n=198) Central/Eastern Europe (n=134) Central/Eastern (C/E) Europe were 3 25 Croatia 680 0.5 97.5 128 67.7 >32 71.8 0.25 94.1 >8 80.9 >64 77.1 colistin, which is nephrotoxic. collected from Croatia, the Czech Citrobacter youngae 1 SR Czech Republic 747 0.5 100 32 76.0 32 79.0 0.12 99.7 >8 79.0 16 81.1 Republic, Greece, Hungary, Poland, Species undefined 6 ) %

( 20

Romania, Russia, and Ukraine. Morganella s Greece 587 2 93.0 >128 69.0 >32 74.5 >16 84.8 >8 76.7 >64 73.3 References e

Morganella morganii t 1. CLSI. Methods for Dilution Antimicrobial Susceptibility Tests for (3%) 578 a . Antimicrobial susceptibility was l o 15 Hungary 638 0.5 99.7 64 73.4 16 78.1 0.12 98.3 >8 80.9 32 82.9 that Grow aerobically. 11th ed. CLSI standard M07. Wayne, PA: Clinical s Providencia stuartii i * 251 and Laboratory Standards Institute; 2018. determined by broth microdilution f o Providencia rettgeri Poland 670 1 98.4 >128 59.7 >32 62.7 0.5 94.0 >8 80.6 >64 67.5 2. The European Committee on Antimicrobial Susceptibility Testing. using CLSI guidelines and interpre- 185 e Breakpoint tables for interpretation of MICs and zone diameters. Version Providencia g 10 a Providencia alcalifaciens 6 t 11.0, 2021. http://www.eucast.org.

ted applying EUCAST 2021 n (3%) Romania 525 1 94.5 >128 63.1 >32 68.2 8 89.0 >8 75.8 >64 69.9 3. Lob SH, Kazmierczak KM, Badal RE, Hackel MA, Bouchillon SK, e c

breakpoints [1,2]. Ceftazidime- Providencia rustigianii 2 r * Biedenbach DJ, Sahm, DF. 2015. Trends in susceptibility of Escherichia e 5 Russia 1,439 2 92.9 >128 45.7 >32 45.7 >16 83.7 >8 86.9 >64 60.3 coli from intra-abdominal infections to ertapenem and comparators in the avibactam was tested with a fixed Species undefined 3 P United States according to data from the SMART program, 2009 to 2013. concentration of 4 mg/L avibactam. Raoultella ornithinolytica Ukraine 288 2 96.5 >128 40.3 >32 40.3 >16 83.0 >8 77.4 >64 63.2 Antimicrob Agents Chemother 59:3606-3610. 18 0 β-lactamase screening by PCR and aAbbreviations: CAZ-AVI, ceftazidime-avibactam; CAZ, ceftazidime; FEP, cefepime; MEM, meropenem; CST, colistin; TZP, Raoultella planticola 8 ≤0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32 64 128 >128 sequencing was performed on Other piperacillin-tazobactam; NS, non-susceptible; MBL-neg, metallo-β-lactamase-negative; R, Resistant. Pantoea agglomerans b (<1%) 3 MIC (mg/L) CST-R subset does not include isolates of the family Morganellaceae or Serratia spp. due to intrinsic CST-resistance. Disclosures isolates with meropenem MIC MBLs were identified in isolates collected in: Belgium (n=4), France (n=2), Germany (n=5), Ireland (n=1), Italy (n=24), Spain This study was sponsored by Pfizer. IHMA received financial support from 3 (n=9), Switzerland (n=1), United Kingdom (n=12), Croatia (n=16), Greece (n=39), Hungary (n=15), Poland (n=11), Romania values >1 mg/L as described *MBLs were identified in 8/12 (66.7%) of isolates collected in Northern/Western Europe and 17/17 (100%) of isolates Pfizer in connection with the study and the development of this poster. ME, Other (n=30), Russia (n=99), and Ukraine (n=10). previously [3]. 7 collected in Central/Eastern Europe testing with ceftazidime-avibactam MICs ≥16 µg/ml. KK, and DS are employees of IHMA. GS is an employee of Pfizer. Dashed line represents the EUCAST 2021 breakpoint for ceftazidime-avibactam (S, susceptible; R, Resistant).

Presented at ECCMID 2021, July 9-12, 2021 Online