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

Michaela Simon; Roman G Gerlach; Yvonne Pfeifer; Niels Pfennigwerth; Sören G Gatermann; Agnes Schröder; Andreas Hiergeist; Axel Hamprecht; Tamara Rügamer; André Gessner; Jonathan Jantsch

doi:10.3389/fmicb.2022.977330

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

Front Microbiol. 2022 Nov 22:13:977330. doi: 10.3389/fmicb.2022.977330. eCollection 2022.

Authors

Michaela Simon^{1

2}, Roman G Gerlach³, Yvonne Pfeifer⁴, Niels Pfennigwerth⁵, Sören G Gatermann⁵, Agnes Schröder^{1

6}, Andreas Hiergeist¹, Axel Hamprecht^{2

7

8

9}, Tamara Rügamer¹, André Gessner¹, Jonathan Jantsch^{1

2}

Affiliations

¹ Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg, Regensburg, Germany.
² Institute for Medical Microbiology, Immunology, and Hygiene, University Hospital Cologne and Faculty of Medicine, University of Cologne, Cologne, Germany.
³ Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität (FAU) Erlangen- Nürnberg, Erlangen, Germany.
⁴ FG13 Nosocomial Pathogens and Antibiotic Resistance, Robert Koch Institute, Wernigerode, Germany.
⁵ Department of Medical Microbiology, German National Reference Centre for Multidrug-Resistant Gram-negative Bacteria, Ruhr-University Bochum, Bochum, Germany.
⁶ Department of Orthodontics, University Hospital Regensburg, Regensburg, Germany.
⁷ Department of Medical Microbiology and Virology, Carl von Ossietzky University Oldenburg, Oldenburg, Germany.
⁸ Institute for Medical Microbiology and Virology, Oldenburg, Germany.
⁹ German Centre for Infection Research, Partner Site Bonn-Cologne, Cologne, Germany.

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.

Keywords: Enterobacterales; Micronaut; Phoenix; Pseudomonas aeruginosa; antimicrobial susceptibility testing; ceftazidime-avibactam; metallo-β-lactamases; zinc.