Activity of aztreonam-avibactam against Enterobacterales resistant to recently approved beta-lactamase inhibitor combinations collected in Europe, Latin America, and the Asia-Pacific Region (2020-2022).

Aztreonam-avibactam is under clinical development for treatment of infections caused by carbapenem-resistant Enterobacterales (CRE), especially those resistant to recently approved β-lactamase inhibitor combinations (BLICs). To evaluate a large collection of CRE isolates, including those non-susceptible to ceftazidime-avibactam, meropenem-vaborbactam, and/or imipenem-relebactam. Overall, 24 580 Enterobacterales isolates were consecutively collected (1/patient) in 2020-2022 from 64 medical centres located in Western Europe (W-EU), Eastern Europe (E-EU), Latin America (LATAM), and the Asia-Pacific region (APAC). Of those, 1016 (4.1%) were CRE. Isolates were susceptibility tested by broth microdilution. CRE isolates were screened for carbapenemase genes by whole genome sequencing. Aztreonam-avibactam inhibited 99.6% of CREs at ≤8 mg/L. Ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-relebactam were active against 64.6%, 57.4%, and 50.7% of CRE isolates, respectively; most of the non-susceptible isolates carried metallo-beta-lactamases. Aztreonam-avibactam was active against ≥98.9% of isolates non-susceptible to these BLICs. The activity of these BLICs varied by region, with highest susceptibility rates observed in W-EU (76.9% for ceftazidime-avibactam, 72.5% for meropenem-vaborbactam, 63.8% for imipenem-relebactam) and the lowest susceptibility rates identified in the APAC region (39.9% for ceftazidime-avibactam, 37.8% for meropenem-vaborbactam, and 27.5% for imipenem-relebactam). The most common carbapenemase types overall were KPC (44.6% of CREs), NDM (29.9%), and OXA-48-like (16.0%). KPC predominated in LATAM (64.1% of CREs in the region) and W-EU (61.1%). MBL occurrence was highest in APAC (59.5% of CREs in the region), followed by LATAM (34.0%), E-EU (28.9%), and W-EU (23.6%). Aztreonam-avibactam demonstrated potent activity against CRE isolates resistant to ceftazidime-avibactam, meropenem-vaborbactam, and/or imipenem-relebactam independent of the carbapenemase produced.

Sader HS ，Carvalhaes CG ，Kimbrough JH ，Mendes RE ，Castanheira M ... -  《-》

Aztreonam/avibactam activity against clinical isolates of Enterobacterales collected in Europe, Asia and Latin America in 2019.

Sader HS ，Carvalhaes CG ，Arends SJR ，Castanheira M ，Mendes RE ... -  《-》

Antimicrobial activity of ceftazidime-avibactam against KPC-2-producing Enterobacterales: a cross-combination and dose-escalation titration study with relebactam and vaborbactam.

Kang MS ，Baek JY ，Ko J-H ，Cho SY ，Lee KY ，Lee YH ，Yang J ，Kim TY ，Huh HJ ，Lee NY ，Huh K ，Kang C-I ，Chung DR ，Peck KR ... -  《Microbiology Spectrum》

Activity of ceftazidime/avibactam, meropenem/vaborbactam and imipenem/relebactam against carbapenemase-negative carbapenem-resistant Enterobacterales isolates from US hospitals.

We investigated the prevalence, resistance mechanisms and activity of ceftazidime/avibactam, meropenem/vaborbactam, imipenem/relebactam and comparator agents against carbapenem-resistant Enterobacterales (CRE) that did not carry carbapenemase genes. Among 304 CRE isolates collected in US hospitals during 2016-2018 (1.1% of the overall Enterobacterales), 45 (14.8%) isolates did not carry carbapenemases. These isolates were mainly Klebsiella aerogenes (n = 11), Enterobacter cloacae (n = 11) and Klebsiella pneumoniae (n = 10). Isolates harboured one to six β-lactam resistance mechanisms (median, three mechanisms). Acquired β-lactamase genes were detected in 21 isolates; blaCTX-M-15 was the most common acquired β-lactamase gene found (14 isolates). All 11 K. aerogenes and 6 E. cloacae isolates overexpressed AmpC. Only one isolate belonging to these species carried acquired β-lactamase genes. Disruptions or reduced expression of both outer membrane proteins (ompC/ompK36 and ompF/ompK35) were detected among 20 isolates. AcrAB-TolC was modestly expressed or overexpressed among 19 isolates from six species. One E. coli isolate produced a CTX-M-15 variant that displayed an increased meropenem minimum inhibitory concentration (MIC) when expressed in a clean background. Most β-lactam agents had limited activity against CRE isolates that did not carry carbapenemases. Ceftazidime/avibactam inhibited all isolates, while imipenem/relebactam and meropenem/vaborbactam inhibited 93.0% (88.9% if Proteus mirabilis is included) and 93.3% of tested isolates at current breakpoints. The resistance mechanisms among CRE isolates that did not produce carbapenemases are complex; β-lactam/β-lactamase inhibitor combinations might have different activity against these isolates depending on their resistance mechanisms and the bacterial species.

Castanheira M ，Doyle TB ，Deshpande LM ，Mendes RE ，Sader HS ... -  《-》

Ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-relebactam activities against multidrug-resistant Enterobacterales from United States Medical Centers (2018-2022).

A total of 35,360 Enterobacterales isolates were consecutively collected from 75 US medical centers in 2018-2022. Among these isolates, 2612 (7.4%) were categorized as multidrug-resistant (MDR). Isolates were susceptibility tested by reference broth microdilution methods. Carbapenem-resistant Enterobacterales (CRE) were screened for carbapenemase (CPE) genes by whole genome sequencing. The highest MDR rates was observed among Klebsiella pneumoniae (12.2%), followed by Raoultella spp. (10.9%) and Providencia stuartii (9.8%). Ceftazidime-avibactam and meropenem-vaborbactam were very active and showed identical susceptibility rates against MDR isolates (97.9%). Imipenem-relebactam (93.5% susceptible [S]) exhibited slightly lower susceptibility rates due to its limited activity against Morganellaceae family. The most active β-lactamase inhibitor combination (BLI) against CRE isolates (n = 310) was ceftazidime-avibactam (84.2%S), followed by meropenem-vaborbactam (81.9%S) and imipenem-relebactam (74.8%S). All 3 BLIs were very active against KPC producers and none were active against MBL producers. Ceftazidime-avibactam exhibited greater activity against OXA-48-type producers than meropenem-vaborbactam and imipenem-vaborbactam.

Sader HS ，Mendes RE ，Duncan L ，Kimbrough JH ，Carvalhaes CG ，Castanheira M ... -  《-》