<i>In Vitro</i> Activities and Inoculum Effects of Ceftazidime-Avibactam and Aztreonam-Avibactam against Carbapenem-Resistant <i>Enterobacterales</i> Isolates from South Korea

• Main Authors: Taeeun Kim, Seung Cheol Lee, Moonsuk Bae, Heungsup Sung, Mi-Na Kim, Jiwon Jung, Min Jae Kim, Sung-Han Kim, Sang-Oh Lee, Sang-Ho Choi, Yang Soo Kim, Yong Pil Chong
• Format: Article
• Language: English
• Published: MDPI AG 2020-12-01
• Series: Antibiotics
• Subjects: carbapenem-resistant <i>Enterobacterales</i>; ceftazidime-avibactam; aztreonam-avibactam; inoculum effect; susceptibility
• Online Access: https://www.mdpi.com/2079-6382/9/12/912

Ceftazidime-avibactam (CAZ-AVI) and aztreonam-avibactam (AZT-AVI) are novel antibiotic combinations active against multidrug-resistant Gram-negative pathogens. This study aimed to evaluate their in vitro activities and inoculum effects in carbapenem-resistant <i>Enterobacterales</i> (CRE), including carbapenemase-producing (CP)-CRE and non-CP-CRE. A total of 81 independent clinical isolates of carbapenem-resistant <i>Escherichia coli </i>and <i>Klebsiella pneumoniae </i>were collected. CAZ-AVI and AZT-AVI minimal inhibitory concentrations (MICs) were evaluated by broth microdilution using standard and high inocula. The inoculum effect was defined as an ≥8-fold increase in MIC with high inoculum. Phenotypic determination of β-lactam resistance mechanism and PCR for carbapenemase genes were performed. Of the 81 CRE isolates, 35 (43%) were CP-CRE. Overall, 73% of the isolates were susceptible to CAZ-AVI, and 95% had low AZT-AVI MICs (≤8 µg/mL). The MIC_50/MIC₉₀s of CAZ-AVI and AZT-AVI were 4/≥512 µg/mL and 0.5/4 µg/mL, respectively. CAZ-AVI was more active against non-CP-CRE than against CP-CRE (susceptibility 80% vs. 63%, <i>p </i>= 0.08; MIC₅₀/MIC₉₀, 2/16 μg/mL vs. 4/≥512 μg/mL), whereas AZT-AVI was more active against CP-CRE (MIC₅₀/MIC₉₀, 0.25/1 μg/mL vs. 0.5/8 μg/mL). All four isolates with high AZT-AVI MIC (≥16 μg/mL) were resistant to CAZ-AVI, but only 18% (4/22) of CAZ-AVI-resistant isolates had high AZT-AVI MIC. The rates of the inoculum effect for CAZ-AVI and AZT-AVI were 18% and 47%, respectively (<i>p </i>< 0.001). Interestingly, the frequency of the AZT-AVI inoculum effect was higher in <i>K. pneumoniae</i> than <i>E. coli</i> (64% vs. 8%, <i>p </i>< 0.001). AZT-AVI is more active against CRE than CAZ-AVI, even in CP-CRE and CAZ-AVI-resistant isolates. The presence of a substantial inoculum effect may contribute to clinical failure in high-inoculum infections treated with AZT-AVI.