Development of EUCAST zone diameter breakpoints and quality control criteria for ceftazidime-avibactam 10-4 μg
Ceftazidime-avibactam disk studies were performed for disk mass selection and for establishing EUCAST quality control ranges and zone diameter breakpoints. The disk mass study included disk diffusion testing with ceftazidime-avibactam 10-4 and 10-6 μg disks and broth microdilution MIC testing for challenge set of 94 Enterobacteriaceae and 45 Pseudomonas aeruginosa. EUCAST SOP 9.0-based QC and MIC-disk correlations studies were followed for development of ceftazidime-avibactam 10-4 μg ranges for Escherichia coli ATCC 25922, P. aeruginosa ATCC 27583, and Klebsiella pneumoniae ATCC 700603 and for zone diameter breakpoint determination. The ceftazidime-avibactam 10-4 and 10-6 μg disks performed similar in comparison to broth microdilution, with zones ≤ 14 mm for all resistant strains. The 10-4 μg disk was selected and used in QC and breakpoint studies. There was minimal variation of ceftazidime-avibactam 10-4 μg QC study results between disks, media, and sites. The QC ranges were within 7 mm for all strains. The zone diameter breakpoint study demonstrated good correlation of MIC and disk results. The established zone diameter breakpoints resulted in false susceptible rates of 1.6 and 4.0% for Enterobacteriaceae and P. aeruginosa. EUCAST selected the ceftazidime-avibactam 10-4 μg disk and established QC ranges for E. coli 25922 of 24–30 mm, P. aeruginosa ATCC 27853 of 21–27 mm, and K. pneumoniae ATCC 700603 of 18–24 mm. The zone diameter breakpoints that correlated best with the MIC breakpoints of susceptible ≤ 8 mg/L and resistant > 8 mg/L were Enterobacteriaceae (S ≥ 13, R < 13 mm) and P. aeruginosa (S ≥ 17, R < 17 mm).
The following investigators and laboratories are recognized for participation in the validation of the quality control ranges and clinical isolates: Andreas Petersen, Statens Serum Institut, Copenhagen, Denmark; Karen Bowker, Southmead Hospital, Bristol, UK; Annarita Mazzariol, Dipartimento di Patologia e Diagnostica, Verona, Italy; Christiane Müllner, analyse BioLab GmbH, Linz, Austria; Maria García-Castillo and Marta Tato Diez, Hospital Universitario Ramón y Cajal, Madrid, Spain; Mandy Wootton, University Hospital of Wales, Cardiff, UK; and Stina Bengtsson, Clinical Microbiology, Central Hospital, Växjö, Sweden.
This study was funded by AstraZeneca Pharmaceuticals LP. AstraZeneca’s rights to ceftazidime-avibactam were acquired by Pfizer in December 2016.
Compliance with ethical standards
Conflict of interest
Gregory Stone was an employee of AstraZeneca and is a current employee of Pfizer. The other authors declare that they have no conflict of interest.
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