Aztreonam/avibactam effect on pharmacodynamic indices for mutant selection ofEscherichia coli and Klebsiella pneumoniaeharbouring serine- and New Delhi metallo-β-lactamases

Abstract

Objectives Ceftazidime/avibactam is not active against MBL-producing bacteria. Combining ceftazidime/avibactam or avibactam with aztreonam can counter the resistance of MBL-producing Enterobacterales. The aim of this study was to evaluate whether the addition of avibactam could reduce or close the mutant selection window (MSW) of aztreonam in Escherichia coli and Klebsiella pneumoniae harbouring MBLs; MSW is a pharmacodynamic (PD) parameter for the selection of emergent resistant mutants. Methods In vitro susceptibility of 19 clinical isolates to ceftazidime/avibactam, aztreonam alone, and in co-administration (aztreonam/ceftazidime/avibactam and aztreonam/avibactam) was determined, as well as the mutant prevention concentration (MPC). The fraction of time within 24 h that the free drug concentration was within the MSW (fTMSW) and the fraction of time that the free drug concentration was above the MPC (fT>MPC) in both plasma and epithelial lining fluid (ELF) were determined from simulations of 10 000 profiles. The joint PTA was used to derive a joint cumulative fraction of response (CFR). Results All isolates were resistant to ceftazidime/avibactam or aztreonam. Combining aztreonam and avibactam or ceftazidime/avibactam resulted in synergistic bactericidal activities against all isolates. Synergism was primarily due to the aztreonam/avibactam combination. For aztreonam/avibactam dosing regimens evaluated in clinical trials, fT>MPC values were >90% and >80%, whereas fTMSW measures were <10% and <20% in plasma and ELF, respectively. The CFR was 100% for aztreonam/avibactam against the collection of clinical isolates. Conclusions Effective antimicrobial combination optimized the PD parameters measuring selection for emergent mutants by increasing fT>MPC and reducing fTMSW.

The combination effect of meropenem/sulbactam/polymyxin-B on the pharmacodynamic parameters for mutant selection windows against carbapenem-resistant Acinetobacter baumannii

“…The clinical isolates were provided by Dr. Yuanqi Zhu. Next-generation sequencing was used to determine the resistance genes in each isolate, as described ( Feng et al, 2021 ). Eleven clinical A. baumannii strains harboring bla OXA-23 were selected.…”

Effects of amikacin, polymyxin-B, and sulbactam combination on the pharmacodynamic indices of mutant selection against multi-drug resistant Acinetobacter baumannii

“…SOAPdenovo2 was used to assemble the qualified reads. Glimmer was applied to predict the coding sequences, and the sequences were further compared against all known drug resistance genes using BLAST to obtain the types of resistance-encoding genes in all studied strains ( Feng et al, 2021 ). E. coli ATCC 25922 and A. baumannii ATCC19606 were selected as quality control strains for antimicrobial susceptibility tests.…”

“…A theory was postulated that the lesser time at which the bacteria spent in MSW would translate to a lesser opportunity for them to develop resistance ( Hesje et al, 2007 ). When MPC converged to MIC for all antibiotics in the combination, this suggests that there is no further resistance development ( Fedrigo et al, 2021 ; Feng et al, 2021 ). Two pharmacodynamic (PD) parameters are often used as an inference of the emergence of resistant mutants: ( Antunes et al, 2014 ) the fraction of time over the 24 h wherein the free drug concentration was within the MSW ( f T MSW ); and ( Maragakis and Perl, 2008 ) the fraction of time over the same period wherein the free drug concentration exceeds the MPC ( f T >MPC ).…”

Drug development concerning metallo-β-lactamases in gram-negative bacteria

“…As shown in Table 1 , in vitro , aztreonam (≤0.03–4 μg/ml)+CAZ-AVI (4 μg/ml of the AVI component) exerts potent synergistic effects against most tested MBL-producing Enterobacteriaceae and few MBL-producing P. aeruginosa , which is superior to aztreonam alone or in combination with other drug combinations, such as aztreonam +amoxillin-clavulanate and aztreonam+ceftolozane-tazobactam (Emeraud et al, 2019 ; Niu et al, 2020 ; Khan et al, 2021 ; Maraki et al, 2021 ). With further research, the synergistic effect of aztreonam+CAZ-AVI on MBL producers was proven to be mainly caused by the combination of aztreonam and AVI (Feng et al, 2021 ). AVI is a novel β-lactamase inhibitor that effectively inhibits class A and C carbapenems (Das et al, 2019 ).…”

“…A series of in vitro studies on the combined effects of aztreonam+AVI against MBLs have been carried out. Aztreonam+AVI (≤0.015–4+4 μg/ml) has strong antibacterial activity on Enterobacteriaceae producing MBLs alone or both MBLs and SBLs (Karlowsky et al, 2017 ; Biagi et al, 2019 ; Niu et al, 2020 ; Zhang et al, 2020 ; Bhatnagar et al, 2021 ; Cervino et al, 2021 ; Feng et al, 2021 ). Karlowsky et al found that aztreonam+AVI (4 μg/ml+4 μg/ml) also has a good inhibitory effect on a small portion of MBL- P. aeruginosa isolates (63/452) (Karlowsky et al, 2017 ).…”