KPC Beta-Lactamases Are Permissive to Insertions and Deletions Conferring Substrate Spectrum Modifications and Resistance to Ceftazidime-Avibactam

Hobson, Claire Amaris; Bonacorsi, Stéphane; Jacquier, Hervé; Choudhury, Alaksh; Magnan, Mélanie; Cointe, Aurélie; Berçot, Béatrice; Tenaillon, Olivier; Birgy, André

doi:10.1128/aac.01175-20

Cited by 32 publications

(33 citation statements)

References 25 publications

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“…In total, 37 mutants with increased CZA MIC were used for this study. Of these, 17 containing insertions or deletions in the KPC gene have been described previously [3], including three in clinical isolates (KPC-25, KPC-29 and KPC-44). Twenty different non-synonymous mutations were also investigated, including three previously described in clinical isolates (KPC-31, KPC-33 and KPC-39), six in in vitro experiments, and 11 that are, to our knowledge, new from this study [8e11] (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…We used the previously described CZA-resistant mutants containing insertions or deletions in the coding region of bla KPC as well as new mutants obtained from in vitro selection [3]. Briefly, three isolates of KPC-producing Enterobacteriaceae were used for in vitro selection of CZA-resistant mutants as previously described.…”

Section: Isolatesmentioning

confidence: 99%

“…Soon after the commercialization of CZA in 2015, resistant mutants were described both in vitro and in vivo, notably Klebsiella pneumoniae carbapenemase (KPC) producers [3,4]. KPC b-lactamase has spread worldwide, challenging the therapeutic management of infected patients.…”

Section: Introductionmentioning

confidence: 99%

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Cross-resistance to cefiderocol and ceftazidime–avibactam in KPC β-lactamase mutants and the inoculum effect

Hobson

Cointe

Jacquier

et al. 2021

Clinical Microbiology and Infection

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Objectives: Ceftazidimeeavibactam (CZA) and cefiderocol are recently commercialized molecules active against highly drug-resistant bacteria, including carbapenem-resistant members of the Enterobacteriaceae. Mutants resistant to CZA have been described, notably in Klebsiella pneumoniae carbapenemase (KPC) producers. Considering the structural similarities between ceftazidime and cefiderocol, we hypothesized that resistance to CZA in KPC-producing members of the Enterobacterales may lead to crossresistance to cefiderocol. Methods: CZA-resistant mutants from three clinical isolates of the Enterobacterales carrying either bla KPC-2 or bla KPC-3 were selected in vitro. Mutants with increased MIC to CZA compared to the ancestral allele were cloned in a pBR322 plasmid and expressed in Escherichia coli TOP10. We evaluated the impact of these mutations on cefiderocol MICs and minimal bactericidal concentrations (MBCs), and we assessed the impact of bacterial inoculum size on cefiderocol MICs. Results: We used 37 KPC mutants with increased CZA MICs. Of these, six have been described previously in clinical isolates. Compared to the wild-type alleles, increases in the cefiderocol MICs of 4-to 32-fold were observed for 75.6% of tested mutants (28/37), MICs reaching up to 4 mg/L in E. coli TOP10 for KPC-31 (D179YeH274Y mutations). MBCs and MICs of cefiderocol were similar, confirming the bactericidal activity of this drug. Finally, when using higher inocula (10 7 CFU/mL), a large increase in cefiderocol MIC was observed, and all isolates were categorized as resistant. Conclusion:We observed that most of the CZA-resistant KPC variants have a possible impact on cefiderocol by increasing the cefiderocol MICs. In addition, cefiderocol is greatly impacted by the inoculum effect, suggesting that precautions should be taken when treating infections with a suspected high inoculum.

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Section: Resultsmentioning

confidence: 99%

Section: Isolatesmentioning

confidence: 99%

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Cross-resistance to cefiderocol and ceftazidime–avibactam in KPC β-lactamase mutants and the inoculum effect

Hobson

Cointe

Jacquier

et al. 2021

Clinical Microbiology and Infection

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“…1B). TR insertions within the KPC Ala to Ser 275 loop have been reported previously (12) including KPC-50, a KPC-3 variant with a three-amino-acid insertion (Glu-Ala-Val) at this exact position (3).…”

Section: Main Textmentioning

confidence: 96%

Characterization of KPC-82, a KPC-2 Variant Conferring Resistance to Ceftazidime-Avibactam in a Carbapenem-Nonsusceptible Clinical Isolate of Citrobacter koseri

Lebreton

Corey

McElheny

et al. 2021

Antimicrob Agents Chemother

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KPC-82 is a KPC-2 variant, identified in a carbapenem non-susceptible Citrobacter koseri that confers high-level resistance to ceftazidime-avibactam. Genomic analysis revealed that bla KPC-82 is carried by a chromosomally integrated Tn 4401 transposon (disrupting porin gene phoE ) and evolved by a 6-nucleotide tandem-repeat duplication causing a two-amino-acid insertion (Ser-Asp) within the Ala 267 -Ser 275 loop. Similar to related KPC variants, KPC-82 showed decreased carbapenemase activity when expressed in a heterologous background and remained susceptible to carbapenem/β-lactamase inhibitor combinations.

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“…Avibactam is currently in clinical use partnered by ceftazidime (CAZ/AVI) and here, mutations in KPC are known to confer resistance. However, such mutations tend to reduce hydrolytic activity to β-lactams other than ceftazidime, including carbapenems and aztreonam (3)(4)(5)(6). Accordingly, it is conceivable that such mutant KPC enzymes might not confer AZT/AVI resistance.…”

Section: Textmentioning

confidence: 99%

Klebsiella pneumoniae mutants resistant to ceftazidime/avibactam plus aztreonam, imipenem/relebactam, meropenem/vaborbactam and cefepime/taniborbactam

Satapoomin

Dulyayangkul

Avison

2021

Preprint

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Using modified Klebsiella pneumoniae clinical isolates, we show that ramR plus ompK36 mutation together with production of the V239G variant KPC-3 confirs resistance to ceftazidime/avibactam plus aztreonam, imipenem/relebactam and meropenem/vaborbactam, but not cefepime/taniborbactam. This is because the V239G variant does not generate collateral β-lactam susceptibility as do many other KPC-3 variants associated with ceftazidime/avibactam resistance. Additional mutation of ompK35 and carriage of a plasmid expressing the OXA-48-like carbapenemase OXA-232 was required to confer cefepime/taniborbactam resistance.

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KPC Beta-Lactamases Are Permissive to Insertions and Deletions Conferring Substrate Spectrum Modifications and Resistance to Ceftazidime-Avibactam

Cited by 32 publications

References 25 publications

Cross-resistance to cefiderocol and ceftazidime–avibactam in KPC β-lactamase mutants and the inoculum effect

Cross-resistance to cefiderocol and ceftazidime–avibactam in KPC β-lactamase mutants and the inoculum effect

Characterization of KPC-82, a KPC-2 Variant Conferring Resistance to Ceftazidime-Avibactam in a Carbapenem-Nonsusceptible Clinical Isolate of Citrobacter koseri

Klebsiella pneumoniae mutants resistant to ceftazidime/avibactam plus aztreonam, imipenem/relebactam, meropenem/vaborbactam and cefepime/taniborbactam

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