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- Title
Emergence of ceftazidime/avibactam non-susceptibility in an MDR Klebsiella pneumoniae isolate.
- Authors
Both, Anna; Büttner, Henning; Huang, Jiabin; Perbandt, Markus; Campos, Cristina Belmar; Christner, Martin; Maurer, Florian P.; Kluge, Stefan; König, Christina; Aepfelbacher, Martin; Wichmann, Dominic; Rohde, Holger; Belmar Campos, Cristina
- Abstract
<bold>Background: </bold>Avibactam is a novel broad-range β-lactamase inhibitor active against Ambler class A (including ESBL and KPC) and some Ambler class C and D (e.g. OXA-48) enzymes. We here report on the emergence of ceftazidime/avibactam resistance in clinical, multiresistant, OXA-48 and CTX-M-14-producing Klebsiella pneumoniae isolate DT12 during ceftazidime/avibactam treatment.<bold>Methods and results: </bold>Comparative whole-genome sequence analysis identified two SNPs in the CTX-M-14-encoding gene leading to two amino acid changes (P170S and T264I). Compared with WT CTX-M-14, expression of the CTX-M-14Δ170Δ264 isoform in Escherichia coli led to a >64- and 16-fold increase in ceftazidime and ceftazidime/avibactam MICs, respectively, functionally linking the observed SNPs and elevated MICs. The mutated CTX-M-14 isoform exhibited augmented ceftazidime hydrolytic activity, which was a reasonable cause for impaired susceptibility to avibactam inhibition. The P170S exchange in CTX-M-14 was found in association with elevated ceftazidime/avibactam MICs for independent K. pneumoniae isolates, but was not sufficient for full resistance. Apparently, additional CTX-M-independent mechanisms contribute to ceftazidime/avibactam resistance in K. pneumoniae DT12.<bold>Conclusions: </bold>This study on the molecular basis of ceftazidime/avibactam resistance in clinical K. pneumoniae emerging in vivo underscores the need for continuous monitoring of ceftazidime/avibactam susceptibility during therapy. Despite sustained inhibition of OXA-48, rapid development of CTX-M-14 isoforms exhibiting augmented ceftazidime hydrolytic activity may limit the usefulness of ceftazidime/avibactam monotherapies in infections caused by isolates carrying blaCTX-M-14 and blaOXA-48.
- Subjects
KLEBSIELLA pneumoniae; CEFTAZIDIME; MULTIDRUG resistance in bacteria; BETA-lactamase inhibitors; MICROBIAL sensitivity tests; THERAPEUTICS; ANTIBIOTICS; DRUG resistance in microorganisms; ENZYME inhibitors; GENOMES; KLEBSIELLA; ORGANIC compounds; KLEBSIELLA infections; SEQUENCE analysis; PHARMACODYNAMICS
- Publication
Journal of Antimicrobial Chemotherapy (JAC), 2017, Vol 72, Issue 9, p2483
- ISSN
0305-7453
- Publication type
journal article
- DOI
10.1093/jac/dkx179