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

Taeeun Kim,Jiwon Jung,Sung-Han Kim,Yong Pil Chong,Seung Cheol Lee,Moonsuk Bae,Sang-Ho Choi,Yang Soo Kim,Min Jae Kim,Sang-Oh Lee,Heungsup Sung,Mi-Na Kim

doi:10.3390/antibiotics9120912

Abstract

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 Enterobacterales (CRE), including carbapenemase-producing (CP)-CRE and non-CP-CRE. A total of 81 independent clinical isolates of carbapenem-resistant Escherichia coli and Klebsiella pneumoniae 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 MIC50/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%, p = 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 (p < 0.001). Interestingly, the frequency of the AZT-AVI inoculum effect was higher in K. pneumoniae than E. coli (64% vs. 8%, p < 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.

Highlights

Carbapenem-resistant Enterobacterales (CRE) challenge pharmaceutical chemists and clinicians on account of their difficult-to-treat resistance and increasing global prevalence [1]
Ceftazidime-avibactam was active against 73% of CRE isolates, and aztreonam-avibactam had a low minimal inhibitory concentrations (MICs) (≤8 μg/mL) against 95% of the CRE isolates
Unlike ceftazidime-avibactam, aztreonam-avibactam was less active against non-CP-CRE isolates than against CP-CRE isolates

Summary

Introduction

Carbapenem-resistant Enterobacterales (CRE) challenge pharmaceutical chemists and clinicians on account of their difficult-to-treat resistance and increasing global prevalence [1]. Due to the limited therapeutic options for CRE infections, the polymyxins (colistin and polymyxin B) are frequently used as last resort drugs. Their high rates of nephrotoxicity, which range from 30%. A new non-β-lactam β-lactamase inhibitor, is an inhibitor of class A β-lactamases, including extended-spectrum β-lactamases (ESBLs) and Klebsiella pneumoniae carbapenemases (KPCs), and class C (AmpC) and some class D (OXA-48). Ceftazidime-avibactam shows promising activity against CRE strains, such as KPC-producing K. pneumoniae and Escherichia coli [4]. Ceftazidime-avibactam is usually not active against class B metallo-β-lactamase (MBL)-producing CRE [4]. After the introduction of ceftazidime-avibactam into clinical use, cases of resistance due to various mechanisms have been increasingly reported [5]

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