Activity of imipenem/relebactam and comparators against KPC-producing Klebsiella pneumoniae and imipenem-resistant Pseudomonas aeruginosa

Delgado-Valverde, Mercedes; Portillo-Calderón, Inés; Alcalde-Rico, Manuel; Conejo, M. Carmen; Hidalgo, Carmen; del Toro Esperón, Carlos; Pascual, Álvaro

doi:10.1007/s10096-023-04735-1

Cited by 3 publications

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References 45 publications

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“…Circular genome visualization was performed using pyCirclize ( Shimoyama, 2022 ). The non-synonymous polymorphisms of genes associated with mutational resistome of P. aeruginosa ( López-Causapé et al., 2017 ) were identifed by calling SNPs with Snippy v4.6.0 software ( https://github.com/tseemann/snippy ), mapping the trimmed raw reads of each bacterial isolate with respect the PAO1 reference genome (NC_002516.2) ( Delgado-Valverde et al., 2024 ). In addition, amino acid sequences were compared with that of susceptible isolates of the same STs using ClustalW.…”

Section: Methodsmentioning

confidence: 99%

Ceftazidime/avibactam resistance is associated with PER-3-producing ST309 lineage in Chilean clinical isolates of non-carbapenemase producing Pseudomonas aeruginosa

Soto,

Alcalde-Rico,

Ugalde

et al. 2024

Front. Cell. Infect. Microbiol.

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IntroductionCeftazidime/avibactam (CZA) is indicated against multidrug-resistant Pseudomonas aeruginosa, particularly those that are carbapenem resistant. CZA resistance in P. aeruginosa producing PER, a class A extended-spectrum β-lactamase, has been well documented in vitro. However, data regarding clinical isolates are scarce. Our aim was to analyze the contribution of PER to CZA resistance in non-carbapenemase-producing P. aeruginosa clinical isolates that were ceftazidime and/or carbapenem non-susceptible.MethodsAntimicrobial susceptibility was determined through agar dilution and broth microdilution, while blaPER gene was screened through PCR. All PER-positive isolates and five PER-negative isolates were analyzed through Whole Genome Sequencing. The mutational resistome associated to CZA resistance was determined through sequence analysis of genes coding for PBPs 1b, 3 and 4, MexAB-OprM regulators MexZ, MexR, NalC and NalD, AmpC regulators AmpD and AmpR, and OprD porin. Loss of blaPER-3 gene was induced in a PER-positive isolate by successive passages at 43°C without antibiotics. ResultsTwenty-six of 287 isolates studied (9.1%) were CZA-resistant. Thirteen of 26 CZA-resistant isolates (50%) carried blaPER. One isolate carried blaPER but was CZA-susceptible. PER-producing isolates had significantly higher MICs for CZA, amikacin, gentamicin, ceftazidime, meropenem and ciprofloxacin than non-PER-producing isolates. All PER-producing isolates were ST309 and their blaPER-3 gene was associated to ISCR1, an insertion sequence known to mobilize adjacent DNA. PER-negative isolates were classified as ST41, ST235 (two isolates), ST395 and ST253. PER-negative isolates carried genes for narrow-spectrum β-lactamases and the mutational resistome showed that all isolates had one major alteration in at least one of the genes analyzed. Loss of blaPER-3 gene restored susceptibility to CZA, ceftolozane/tazobactam and other β-lactamsin the in vitro evolved isolate. DiscussionPER-3-producing ST309 P. aeruginosa is a successful multidrug-resistant clone with blaPER-3 gene implicated in resistance to CZA and other β-lactams.

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Section: Methodsmentioning

confidence: 99%

Ceftazidime/avibactam resistance is associated with PER-3-producing ST309 lineage in Chilean clinical isolates of non-carbapenemase producing Pseudomonas aeruginosa

Soto,

Alcalde-Rico,

Ugalde

et al. 2024

Front. Cell. Infect. Microbiol.

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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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AmpC induction by imipenem in Pseudomonas aeruginosa occurs in the absence of OprD and impacts imipenem/relebactam susceptibility

Freed, Jr,

Hanson

2024

Microbiol Spectr

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In the United States, carbapenem resistance in Pseudomonas aeruginosa is linked to the regulation of chromosomal resistance determinants, AmpC and OprD. The β-lactamase AmpC requires overexpression and genetic modifications to be capable of inhibiting imipenem activity. The outer membrane porin OprD can be downregulated or undergo genetic modifications that strongly correlate with imipenem non-susceptibility. Co-administration of imipenem and the β-lactamase inhibitor, relebactam, can lower imipenem minimal inhibitory concentrations and restore susceptibility. However, it is not understood how this occurs in P. aeruginosa isolates that do not overproduce AmpC or produce a functional OprD for imipenem entry. Therefore, we investigated whether imipenem could enter P. aeruginosa in the absence of OprD and whether any of the chromosomal β-lactamases (AmpC, OXA-50, and PIB-1) contributed to imipenem and/or imipenem/relebactam non-susceptibility. This investigation evaluated 17 imipenem non-susceptible clinical isolates and three laboratory strains of PAO1, two of which were porin transposon mutants for either oprD or opdP . Expression of OXA-50 and PIB-1 RNA was similar to PAO1. However, all 20 isolates exhibited bla ampC induction under sublethal exposure to imipenem. This occurred in the absence of detectable OprD protein in 18 isolates. Collectively, our data identify that (i) OprD was not the only channel required for imipenem entry and (ii) imipenem susceptibility can be restored by imipenem/relebactam due to the interaction between relebactam and bla ampC overexpression due to imipenem induction. IMPORTANCE Infections caused by Pseudomonas aeruginosa are associated with high mortality and worsened clinical outcomes. The carbapenem, imipenem, has been combined with the β-lactamase inhibitor relebactam to treat carbapenem-resistant P. aeruginosa . Downregulation of the outer membrane porin, OprD is the major mechanism of imipenem resistance; however, relebactam inhibits the chromosomally encoded AmpC β-lactamase. We investigated how relebactam was able to reduce P. aeruginosa imipenem minimal inhibitory concentrations (MICs) in isolates in which OprD was downregulated. Our data show that imipenem is capable of entering the cell in the absence of OprD and capable of inducing the AmpC β-lactamase. The induction of AmpC provides a substrate for relebactam, impacting the imipenem MIC. The data presented support the use of an alternative porin(s) for entry of imipenem. This study provides the basis for further investigation into modifications of imipenem or similar molecules that would increase the affinity for other porins in isolates resistant to imipenem.

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Activity of imipenem/relebactam and comparators against KPC-producing Klebsiella pneumoniae and imipenem-resistant Pseudomonas aeruginosa

Cited by 3 publications

References 45 publications

Ceftazidime/avibactam resistance is associated with PER-3-producing ST309 lineage in Chilean clinical isolates of non-carbapenemase producing Pseudomonas aeruginosa

Ceftazidime/avibactam resistance is associated with PER-3-producing ST309 lineage in Chilean clinical isolates of non-carbapenemase producing Pseudomonas aeruginosa

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

AmpC induction by imipenem in Pseudomonas aeruginosa occurs in the absence of OprD and impacts imipenem/relebactam susceptibility

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