In vitro and in vivo Antimicrobial Activities of Ceftazidime/Avibactam Alone or in Combination with Aztreonam Against Carbapenem-Resistant Enterobacterales

Guoping Lu; Hao Tang; Zhaoxin Xia; Wensu Yang; Huaming Xu; Zhen Liu; Shenwang Ni; Zhaofei Wang; Jilu Shen

doi:10.2147/IDR.S385240

In vitro and in vivo Antimicrobial Activities of Ceftazidime/Avibactam Alone or in Combination with Aztreonam Against Carbapenem-Resistant Enterobacterales

Infect Drug Resist. 2022 Dec 5:15:7107-7116. doi: 10.2147/IDR.S385240. eCollection 2022.

Authors

Guoping Lu^{1

2}, Hao Tang³, Zhaoxin Xia¹, Wensu Yang¹, Huaming Xu¹, Zhen Liu¹, Shenwang Ni¹, Zhaofei Wang¹, Jilu Shen¹

Affiliations

¹ Department of Laboratory Medicine, The First Affiliated Hospital of Anhui Medical University; Anhui Public Health Clinical Center, Hefei, People's Republic of China.
² Department of Laboratory Medicine, The Affiliated Fuyang Hospital of Anhui Medical University, Fuyang, People's Republic of China.
³ Department of Laboratory Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China.

Abstract

Introduction: To examine the in vitro and in vivo antimicrobial activities of ceftazidime/avibactam (CZA) alone or in combination with aztreonam (ATM) against KPC-, NDM-, IMP-, KPC+IMP-, KPC+NDM-producing strains.

Methods: A total of 67 clinical non-repetitive carbapenem-resistant Enterobacterales (CRE) strains were selected for the microdilution broth method that was performed to analyze the minimal inhibitory concentration (MIC) and the combination antimicrobial susceptibility test using checkerboard titration method. The fractional inhibitory concentration (FIC) was calculated to determine the antimicrobial effect. The time-kill assays and the mouse infection model were used to study the bactericidal effect and therapeutic effect of CZA alone or in combination with ATM.

Results: The CZA minimal inhibitory concentration (MIC) values of CZA revealed that 29 KPC-producing strains and 1 OXA-producing strain were ≤4µg/mL. The CZA MIC values of 37 metal-β-lactamase (MBLs)-producing strains such as NDM-, IMP-, KPC+IMP-, KPC+NDM-producing strains were ≥128µg/mL, after combining with ATM, the FIC values were all below 0.51. The time-kill assays revealed that CZA at various concentrations of 2, 4 and 8 MIC showed significant bactericidal efficiency to the KPC-producing strains. For NDM-, IMP-producing strains, no colony growth was detected after 8 hours of incubation with CZA in combination with ATM. Six percent of the mice in the treatment group and 58% of the mice in the infection group died within 3 days.

Conclusion: Our in vitro results showed that CZA had a good antimicrobial effect on the KPC-producing and OXA-producing strains. CZA combined with ATM showed synergistic bacteriostatic or bactericidal activity against NDM-, IMP-, KPC+IMP-, KPC+NDM-producing strains. The combination of CZA and ATM reduced mortality and prolonged lifespan of mice infected with NDM-, IMP-, KPC+IMP-, and KPC+NDM-producing strains, which provides fundamental knowledge for improving treatment strategies and initializing clinical trials.

Keywords: FIC; carbapenem-resistant Enterobacterales; ceftazidime/avibactam; combination therapy.

Grants and funding

This work was funded through a grant from Anhui Provincial Department of Education for University cooperative research and public health collaborative innovation project in Anhui Province in 2020 (Grant No. GXXT-2020-016) and a grant from Anhui Provincial Health Commission for key scientific research projects in 2021 (Grant No.AHWJ2021a011) and major natural science research projects of colleges and universities in Anhui Province in 2021 (Grant No. KJ2021ZD0032).