Successive Emergence of Ceftazidime-Avibactam Resistance through Distinct Genomic Adaptations in bla KPC-2 -Harboring Klebsiella pneumoniae Sequence Type 307 Isolates

• DOI: 10.1128/aac.02101-17
• Publication Date: 2017-12-18T15:11:27Z
• Authors: Marla J. Giddins; Nenad Macesic; Medini K. Annavaj...; Stephania Stump; Sabrina Khan; Thomas H. McConville; Monica Mehta; Angela Gomez-Simm...; Anne-Catrin Uhlemann
• Keywords: Ceftazidime/avibactam; Sequence (biology); Avibactam; Klebsiella

ABSTRACT Ceftazidime-avibactam (CAZ-AVI) is a promising novel treatment for infections caused by carbapenem-resistant Enterobacteriaceae (CRE). Despite improved outcomes compared to those achieved with aminoglycoside- and colistin-based regimens, the rapid evolution of CAZ-AVI resistance during has previously been reported in Klebsiella pneumoniae sequence type 258 (ST258) bla KPC-3 -harboring isolates. Here, we report stepwise isolation two phenotypically distinct CAZ-AVI-resistant isolates from patient pancreatitis. All susceptible ( n = 3) resistant 5) were ST307 clonal background, rapidly emerging clone. Taking advantage short-read Illumina long-read Oxford Nanopore sequencing full-length assembly core chromosome plasmids, demonstrate that first occurred through 532G → T KPC-2 point mutation (D179Y protein substitution) following only 12 days exposure. While subsequent exhibited substantially decreased meropenem (MEM) MICs (≤2 μg/ml), later cultures demonstrated second phenotype lower MIC (12 μg/ml) but also MEM (MIC > 128 μg/ml). These CAZ-AVI- MEM-resistant showed evidence multiple genomic adaptations, mainly insertions deletions. This included amplification transposition wild-type into plasmid, an IS 1 insertion upstream ompK36 , disruption rfb gene locus these Our findings illustrate potential emerge non- K. ST258 backgrounds alternative KPC variants. results raise concerns about strong selective pressures incurred carbapenemase inhibitors, such as avibactam, on considered invulnerable resistance. There urgent need further characterize non-KPC-mediated modes carbapenem intrinsic bacterial factors facilitate emergence treatment.