Ceftazidime-Avibactam Activity against a Challenge Set of Carbapenem-Resistant Enterobacterales: Ompk36 L3 Alterations and β-Lactamases with Ceftazidime Hydrolytic Activity Lead to Elevated MIC Values.

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Ceftazidime-Avibactam Activity against a Challenge Set of Carbapenem-Resistant Enterobacterales: Ompk36 L3 Alterations and β-Lactamases with Ceftazidime Hydrolytic Activity Lead to Elevated MIC Values.

Int J Antimicrob Agents. 2020 May 14;:106011

Authors: Castanheira M, Doyle TB, Hubler C, Sader HS, Mendes RE

Abstract
Ceftazidime-avibactam activity against carbapenem-resistant Enterobacterales (CRE) clinical isolates and resistance mechanisms among non-metallo β-lactamase (MBL) producers displaying ceftazidime-avibactam MIC values at 4 mg/L was studied. CRE isolates (286/8161 Enterobacterales) collected in Asia-Pacific, Europe and Latin America during 2016 were screened for carbapenemase genes. Selected isolates were susceptibility tested for ceftazidime-avibactam in the presence/absence of phenylalanine-arginyl β-naphthylamide (PAβN) and polymyxin B nonapeptide (PMBN). Genome sequences were investigated for the integrity of outer membrane protein (OMP) genes and multilocus sequence typing. qRT-PCR assays were conducted to determine expression of acrA, ampC, and OMP genes. Ceftazidime-avibactam inhibited 99.2% of the Enterobacterales, 78.7% (225) of the 286 CRE, and 100% of 226 non-MBL producers. Among carbapenemase producers (85.3%; 244/286), the most common gene was blaKPC (76 blaKPC-3 and 46 blaKPC-2), followed by blaOXA-48-like (26.7%) and blaNDM (20.9%). Ceftazidime-avibactam MIC values of 4 mg/L were noted among 14 Klebsiella pneumoniae (13 carrying blaKPC and 1 blaCTX-M-15) mostly from Italy and Brazil and 1 Klebsiella aerogenes overexpressing ampC. PAβN did not significantly decrease ceftazidime-avibactam results, but adding PMBN significantly decreased the MIC results for the combination. All K. pneumoniae isolates had a premature stop codon at OmpK35 and most isolates had L3 alterations of OmpK36, low expression of this gene, or OmpC disruption (K. aerogenes). Nine K. pneumoniae isolates belonged to clonal complex 258 and displayed intrahospital clonality. Ceftazidime-avibactam is an important addition to the armamentarium against multidrug-resistant organisms, and elevated MIC results for this combination seem to be associated with L3 ompK36 alterations and β-lactamases able to hydrolyse ceftazidime.

PMID: 32417206 [PubMed - as supplied by publisher]