Increased zinc levels facilitate phenotypic detection of ceftazidime-avibactam resistance in metallo-β-lactamase-producing Gram-negative bacteria

Abstract

Ceftazidime-avibactam is one of the last resort antimicrobial agents for the treatment of carbapenem-resistant, Gram-negative bacteria. Metallo-β-lactamase-producing bacteria are considered to be ceftazidime-avibactam resistant. Here, we evaluated a semi-automated antimicrobial susceptibility testing system regarding its capability to detect phenotypic ceftazidime-avibactam resistance in 176 carbapenem-resistant, metallo-β-lactamase-producing Enterobacterales and Pseudomonas aeruginosa isolates. Nine clinical isolates displayed ceftazidime-avibactam susceptibility in the semi-automated system and six of these isolates were susceptible by broth microdilution, too. In all nine isolates, metallo-β-lactamase-mediated hydrolytic activity was demonstrated with the EDTA-modified carbapenemase inactivation method. As zinc is known to be an important co-factor for metallo-β-lactamase activity, test media of the semi-automated antimicrobial susceptibility testing system and broth microdilution were supplemented with zinc. Thereby, the detection of phenotypic resistance was improved in the semi-automated system and in broth microdilution. Currently, ceftazidime-avibactam is not approved as treatment option for infections by metallo-β-lactamase-producing, Gram-negative bacteria. In infections caused by carbapenem-resistant Gram-negatives, we therefore recommend to rule out the presence of metallo-β-lactamases with additional methods before initiating ceftazidime-avibactam treatment.

Surface water in Lower Saxony: A reservoir for multidrug-resistant Enterobacterales

“…In our study, all CPE isolates were resistant to ceftolozane/tazobactam as expected, while only the metallo-β-lactamase-producing isolates displayed resistance to ceftazidime/avibactam, which is in line with recently published data [ [38] , [39] , [40] ]. Interestingly, two Citrobacter isolates producing both KPC-2 and VIM-1 tested susceptible to imipenem/relebactam (MIC 2 mg/L).…”

“…The borderline susceptibility of these isolates can therefore likely be explained by the inhibition of KPC and AmpC by relebactam, while expression of VIM-1 was not high enough to confer full resistance to imipenem. Of note, imipenem and imipenem-relebactam MICs can be relatively low (≤2 mg/L) in VIM-producing Citrobacter freundii isolates, as previously reported in clinical isolates from Germany [ [40] , [41] , [42] , [43] ].…”

Treatment of a challenging NDM and OXA-48-producing Klebsiella pneumoniae causing skin and soft tissue infection and exhibiting resistance to the combination of Ceftazidime-Avibactam and Aztreonam: A case report

“…Although a meta-analysis of 15 clinical trials showed that tigecycline is associated with higher rate of mortality compared to alternative regimens [7] , subsequent data showed that mortality difference diminished when high dose tigecycline is used (200 mg IV as a single dose followed 100 mg IV every 12 h) [8] . Other possibilities for successful treatment with CZA-ATM could be discordance between MICs measured in vitro and the in vivo activity of CZA against NDMs [9] , [10] , [11] .…”

Multifactorial resistance mechanisms associated with resistance to ceftazidime-avibactam in clinical Pseudomonas aeruginosa isolates from Switzerland

“…( World Health Organization, 2017 ; Horcajada et al., 2019 ). Ceftazidime-avibactam is one of the last resort antimicrobial agents for the treatment of carbapenem-resistant, Gram-negative bacteria ( Simon et al., 2022 ). Reports on carbapenem-resistant P. aeruginosa (CRPA) have increased significantly in recent years and caused much concern, particularly since CRPA infections have been shown to be a significant risk factor for patient mortality ( Buehrle et al., 2017 ).…”