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

• Main Authors: Taeeun Kim (Author), Seung Cheol Lee (Author), Moonsuk Bae (Author), Heungsup Sung (Author), Mi-Na Kim (Author), Jiwon Jung (Author), Min Jae Kim (Author), Sung-Han Kim (Author), Sang-Oh Lee (Author), Sang-Ho Choi (Author), Yang Soo Kim (Author), Yong Pil Chong (Author)
• Format: Book
• Published: MDPI AG, 2020-12-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/antibiotics9120912; 2079-6382
• Keywords: carbapenem-resistant <i>Enterobacterales</i>; ceftazidime-avibactam; aztreonam-avibactam; inoculum effect; susceptibility; Therapeutics. Pharmacology; RM1-950
• Source: Antibiotics, Vol 9, Iss 12, p 912 (2020)

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.