<i>In Vitro</i>
            Mechanisms of Resistance Development to Imipenem-Relebactam in KPC-Producing Klebsiella pneumoniae

Findlay, Jacqueline; Rens, Céline; Poirel, Laurent; Nordmann, Patrice

doi:10.1128/aac.00918-22

Cited by 13 publications

(9 citation statements)

References 27 publications

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“…IS 5 insertions in ompK36 decrease ompK36 expression and have been previously validated as a cause of elevated imipenem/relebactam MICs. 16 , 25 Imipenem/relebactam MICs were less impacted by isolates that harboured a GD duplication in ompK36 , and in vitro killing was similar among isolates with either WT or GD duplication genotypes. We propose the activity of imipenem/relebactam is less impacted by the constriction of porin channels mediated by GD duplication, but significantly impacted by decreased ompK36 expression caused by IS 5 insertions.…”

Section: Discussionmentioning

confidence: 95%

“… 29 Similar observations have been noted for imipenem/relebactam resistance, where bla KPC copy number and loss-of-function ompK36 mutations are selected in vitro . 16 A key difference between the agents is that mutations in bla KPC refractory to relebactam inhibition were selected with imipenem/relebactam, but not meropenem/vaborbactam. 16 , 29 …”

Section: Discussionmentioning

confidence: 99%

“… 16 A key difference between the agents is that mutations in bla KPC refractory to relebactam inhibition were selected with imipenem/relebactam, but not meropenem/vaborbactam. 16 , 29 …”

Section: Discussionmentioning

confidence: 99%

“…Loss-of-function mutations in ompK35 are common among KPC- Kp. 7 , 16 ompK36 genotypes, on the other hand, vary significantly among clinical isolates. Two major mutations have been described in KPC -Kp.…”

Section: Introductionmentioning

confidence: 99%

“…This insertion is known to constrict the inner pore diameter and subsequently limit intake of nutrients as well as antibiotics like the carbapenems. 15 , 16 It is unclear if other reported mutations or insertions in ompK36 impact the activity of carbapenems, or more specifically the activity of ceftazidime/avibactam, imipenem/relebactam or meropenem/vaborbactam.…”

Section: Introductionmentioning

confidence: 99%

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Impact ofompk36genotype and KPC subtype on thein vitroactivity of ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam against KPC-producingK. pneumoniaeclinical isolates

Rogers

Kline

Griffith

et al. 2023

JAC-Antimicrobial Resistance

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Objectives The availability of new β-lactam/β-lactamase inhibitors ceftazidime/avibactam, meropenem/vaborbactam and imipenem/relebactam have redefined contemporary treatment of Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) infections. We aimed to characterize and contrast the in vitro activity of these agents against genetically diverse KPC-Kp clinical isolates. Methods We analysed genomes of 104 non-consecutive KPC-Kp isolates and compared the in vitro antibiotic activity by KPC subtype and ompK36 genotype. MICs were determined in triplicate by CLSI methods. Twenty representative isolates were selected for time–kill analyses against physiological steady-state and trough concentrations, as well as 4× MIC for each agent. Results Fifty-eight percent and 42% of isolates harboured KPC-2 and KPC-3, respectively. OmpK36 mutations were more common among KPC-2- compared with KPC-3-producing Kp (P < 0.0001); mutations were classified as IS5 insertion, glycine-aspartic acid insertion at position 134 (GD duplication) and other mutations. Compared to isolates with WT ompK36, ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam MICs were elevated for isolates with IS5 by 2-, 4- and 16-fold, respectively (P < 0.05 for each). Against isolates with GD duplication, imipenem/relebactam and meropenem/vaborbactam MICs were increased, but ceftazidime/avibactam MICs were not. In time–kill studies, ceftazidime/avibactam-mediated killing correlated with ceftazidime/avibactam MICs, and did not vary across ompK36 genotypes. Imipenem/relebactam was not bactericidal against any isolate at trough concentrations. At steady-state imipenem/relebactam concentrations, regrowth occurred more commonly for isolates with IS5 mutations. Log-kills were lower in the presence of meropenem/vaborbactam for isolates with GD duplication compared with IS5 mutations. Conclusions Our investigation identified key genotypes that attenuate, to varying degrees, the in vitro activity for each of the new β-lactam/β-lactamase inhibitors. Additional studies are needed to translate the importance of these observations into clinical practice.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

“… 16 A key difference between the agents is that mutations in bla KPC refractory to relebactam inhibition were selected with imipenem/relebactam, but not meropenem/vaborbactam. 16 , 29 …”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Impact ofompk36genotype and KPC subtype on thein vitroactivity of ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam against KPC-producingK. pneumoniaeclinical isolates

Rogers

Kline

Griffith

et al. 2023

JAC-Antimicrobial Resistance

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In vivo development of resistance to novel β-lactam/β-lactamase inhibitor combinations in KPC-producing Klebsiella pneumoniae infections: a case series

Boattini,

Bianco,

Comini

et al. 2024

Eur J Clin Microbiol Infect Dis

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Introduction Understanding the dynamics that may characterize the emergence of KPC variants with resistance to novel β-lactam/β-lactamase inhibitor combinations (βL/βLICs) represents a challenge to be overcome in the appropriate use of recently introduced antibiotics. Methods Retrospective case series describing development of multiple resistance to novel βL/βLICs in patients with KPC-producing Klebsiella pneumoniae (KPC-Kp) infections treated with these drugs. Clinical-microbiological investigation and characterization of longitudinal strains by Whole-Genome Sequencing were performed. Results Four patients with KPC-Kp bloodstream infections were included. Most frequent clinical features were kidney disease, obesity, cardiac surgery as reason for admission, ICU stay, treatment with ceftazidime/avibactam, and pneumonia and/or acute kidney injury needing renal replacement therapy as KPC-Kp sepsis-associated complications. The development of resistance to ceftazidime/avibactam was observed in four longitudinal strains (three of which were co-resistant to aztreonam/avibactam and cefiderocol) following treatments with ceftazidime/avibactam (n = 3) or cefiderocol (n = 1). Resistance to meropenem/vaborbactam and imipenem/cilastatin/relebactam was observed in one case after exposure to ceftazidime/avibactam and imipenem/cilastatin/relebactam. Resistome analysis showed that resistance to novel βL/βLICs was related to specific mutations within blaKPC carbapenemase gene (D179Y mutation [KPC-33]; deletion Δ242-GT-243 [KPC-14]) in three longitudinal strains, while porin loss (truncated OmpK35 and OmpK36 porins) was observed in one case. Conclusion Therapy with novel βL/βLICs or cefiderocol may lead to the selection of resistant mutants in the presence of factors influencing the achievement of PK/PD targets. KPC variants are mainly associated with resistance to ceftazidime/avibactam, and some of them (e.g. KPC-14) may also be associated with reduced susceptibility to aztreonam/avibactam and/or cefiderocol. Loss of function of the OmpK35 and OmpK36 porins appears to play a role in the development of resistance to meropenem/vaborbactam and/or imipenem/relebactam, but other mechanisms may also be involved.

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In vitro development of imipenem/relebactam resistance in KPC-producing Klebsiella pneumoniae involves multiple mutations including OmpK36 disruption and KPC modification

Gato

Guijarro-Sánchez

Alonso-García

et al. 2023

International Journal of Antimicrobial Agents

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In Vitro Mechanisms of Resistance Development to Imipenem-Relebactam in KPC-Producing Klebsiella pneumoniae

Cited by 13 publications

References 27 publications

Impact ofompk36genotype and KPC subtype on thein vitroactivity of ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam against KPC-producingK. pneumoniaeclinical isolates

Impact ofompk36genotype and KPC subtype on thein vitroactivity of ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam against KPC-producingK. pneumoniaeclinical isolates

In vivo development of resistance to novel β-lactam/β-lactamase inhibitor combinations in KPC-producing Klebsiella pneumoniae infections: a case series

In vitro development of imipenem/relebactam resistance in KPC-producing Klebsiella pneumoniae involves multiple mutations including OmpK36 disruption and KPC modification

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