A novel KPC-113 variant conferring carbapenem and ceftazidime-avibactam resistance in a multidrug-resistant Pseudomonas aeruginosa isolate

Yang, Qing; Li, Yue; Li, Fang; Lei, Tailong; Cai, Heng; Hua, Xiaoting; Zheng, Min; Yu, Yunsong

doi:10.1016/j.cmi.2022.10.013

Cited by 8 publications

(3 citation statements)

References 25 publications

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“…Although a limitation of this study is the lack of kinetic data, shortly after NCBI designation of the novel bla KPC allele identified in the CZA-resistant K. pneumoniae strain 330 as bla KPC-113 (GenBank accession number: OM728506.1), a report from China described the presence and kinetic properties of KPC-113, identified in Pseudomonas aeruginosa , confirming considerable hydrolyzing abilities to carbapenems and ceftazidime and the significantly weakened inhibitory effect of avibactam ( 33 ).…”

Section: Observationmentioning

confidence: 85%

Emergence of KPC-113 and KPC-114 variants in ceftazidime-avibactam-resistant Klebsiella pneumoniae belonging to high-risk clones ST11 and ST16 in South America

Vásquez-Ponce,

Bispo,

Becerra

et al. 2023

Microbiol Spectr

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Two novel variants of Klebsiella pneumoniae carbapenemase (KPC) associated with resistance to ceftazidime-avibactam (CZA) and designated as KPC-113 and KPC-114 by NCBI were identified in 2020, in clinical isolates of Klebsiella pneumoniae in Brazil. While K. pneumoniae of ST16 harbored the bla KPC-113 variant on an IncFII-IncFIB plasmid, K. pneumoniae of ST11 carried the bla KPC-114 variant on an IncN plasmid. Both isolates displayed resistance to broad-spectrum cephalosporins, β-lactam inhibitors, and ertapenem and doripenem, whereas K. pneumoniae producing KPC-114 showed susceptibility to imipenem and meropenem. Whole-genome sequencing and in silico analysis revealed that KPC-113 presented a Gly insertion between Ambler positions 264 and 265 (R264_A265insG), whereas KPC-114 displayed two amino acid insertions (Ser-Ser) between Ambler positions 181 and 182 (S181_P182insSS) in KPC-2, responsible for CZA resistance profiles. Our results confirm the emergence of novel KPC variants associated with resistance to CZA in international clones of K. pneumoniae circulating in South America. IMPORTANCE KPC-2 carbapenemases are endemic in Latin America. In this regard, in 2018, ceftazidime-avibactam (CZA) was authorized for clinical use in Brazil due to its significant activity against KPC-2 producers. In recent years, reports of resistance to CZA have increased in this country, limiting its clinical application. In this study, we report the emergence of two novel KPC-2 variants, named KPC-113 and KPC-114, associated with CZA resistance in Klebsiella pneumoniae strains belonging to high-risk clones ST11 and ST16. Our finding suggests that novel mutations in KPC-2 are increasing in South America, which is a critical issue deserving active surveillance.

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Section: Observationmentioning

confidence: 85%

Emergence of KPC-113 and KPC-114 variants in ceftazidime-avibactam-resistant Klebsiella pneumoniae belonging to high-risk clones ST11 and ST16 in South America

Vásquez-Ponce,

Bispo,

Becerra

et al. 2023

Microbiol Spectr

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“…A retrospective study from seven hospitals in China found that 40% (151/374) of CRPA strains contained the bla KPC-2 gene ( Zhu et al, 2021 ). Recently, a novel KPC variant KPC-113 from a clinical Pseudomonas aeruginosa was reported to mediate both CAZ–AVI resistance and carbapenem resistance ( Yang et al, 2022a ). However, the specific mechanism of Pseudomonas aeruginosa to CAZ–AVI-resistance needs to be further investigated.…”

Section: Discussionmentioning

confidence: 99%

The dilemma of antibiotic susceptibility and clinical decision-making in a multi-drug-resistant Pseudomonas aeruginosa bloodstream infection

Chen

et al. 2023

Front. Pharmacol.

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Objective: How to choose the appropriate antibiotics and dosage has always been a difficult issue during the treatment of multi-drug-resistant bacterial infections. Our study aims to resolve this difficulty by introducing our multi-disciplinary treatment (MDT) clinical decision-making scheme based on rigorous interpretation of antibiotic susceptibility tests and precise therapeutic drug monitoring (TDM)-guided dosage adjustment.Method: The treatment course of an elderly patient who developed a multi-drug-resistant Pseudomonas aeruginosa (MDRPA) bloodstream infection from a brain abscess was presented.Results: In the treatment process, ceftazidime–avibactam (CAZ–AVI) was used empirically for treating the infection and clinical symptoms improved. However, the follow-up bacterial susceptibility test showed that the bacteria were resistant to CAZ–AVI. Considering the low fault tolerance of clinical therapy, the treatment was switched to a 1 mg/kg maintenance dose of susceptible polymyxin B, and TDM showed that the AUC24h, ss of 65.5 mgh/L had been achieved. However, clinical symptoms were not improved after 6 days of treatment. Facing the complicated situation, the cooperation of physicians, clinical pharmacologists, and microbiologists was applied, and the treatment finally succeeded with the pathogen eradicated when polymyxin B dose was increased to 1.4 mg/kg, with the AUC24h, ss of 98.6 mgh/L.Conclusion: MDT collaboration on the premise of scientific and standardized drug management is helpful for the recovery process in patients. The empirical judgment of doctors, the medication recommendations from experts in the field of TDM and pharmacokinetics/pharmacodynamics, and the drug susceptibility results provided by the clinical microbiology laboratory all provide the direction of treatment.

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“…The knowledge gaps to be filled in this context are mostly related to the intrinsic burden of specific β-lactamases, being of great interest to confirm that globally disseminated enzymes are virtually cost-free unlike specific amino acid variants, that could be associated with great costs, fact determining their limited appearance. In this regard, particularly interesting would be the analysis of fitness costs associated with horizontal β-lactamase variants (mainly OXA-2, OXA-10, and KPC-2/−3 derivatives) that are progressively arising as novel resistance determinants pushed by the selective pressure exerted by recently introduced antipseudomonal drugs such as ceftolozane/tazobactam, ceftazidime/avibactam, and imipenem/relebactam, which have never been studied from the fitness/virulence impact perspective ( Fraile-Ribot et al, 2018 ; Arca-Suárez et al, 2019 , 2021 ; Faccone et al, 2022 ; Lasarte-Monterrubio et al, 2022 ; Tu et al, 2022 ; Yang et al, 2023 ). Finally, it would also be desirable to ascertain whether or not certain plasmid-encoded enzymes are linked to genes responsible for burden-alleviating mechanisms, which could therefore become interesting therapeutic objectives.…”

Section: Horizontally-acquired Resistancementioning

confidence: 99%

The balance between antibiotic resistance and fitness/virulence in Pseudomonas aeruginosa: an update on basic knowledge and fundamental research

Jordana-Lluch,

Barceló,

Escobar-Salom

et al. 2023

Front. Microbiol.

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The interplay between antibiotic resistance and bacterial fitness/virulence has attracted the interest of researchers for decades because of its therapeutic implications, since it is classically assumed that resistance usually entails certain biological costs. Reviews on this topic revise the published data from a general point of view, including studies based on clinical strains or in vitro-evolved mutants in which the resistance phenotype is seen as a final outcome, i.e., a combination of mechanisms. However, a review analyzing the resistance/fitness balance from the basic research perspective, compiling studies in which the different resistance pathways and respective biological costs are individually approached, was missing. Here we cover this gap, specifically focusing on Pseudomonas aeruginosa, a pathogen that stands out because of its extraordinary capacity for resistance development and for which a considerable number of recent and particular data on the interplay with fitness/virulence have been released. The revised information, split into horizontally-acquired vs. mutation-driven resistance, suggests a great complexity and even controversy in the resistance-fitness/virulence balance in the acute infection context, with results ranging from high costs linked to certain pathways to others that are seemingly cost-free or even cases of resistance mechanisms contributing to increased pathogenic capacities. The elusive mechanistic basis for some enigmatic data, knowledge gaps, and possibilities for therapeutic exploitation are discussed. The information gathered suggests that resistance-fitness/virulence interplay may be a source of potential antipseudomonal targets and thus, this review poses the elementary first step for the future development of these strategies harnessing certain resistance-associated biological burdens.

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A novel KPC-113 variant conferring carbapenem and ceftazidime-avibactam resistance in a multidrug-resistant Pseudomonas aeruginosa isolate

Cited by 8 publications

References 25 publications

Emergence of KPC-113 and KPC-114 variants in ceftazidime-avibactam-resistant Klebsiella pneumoniae belonging to high-risk clones ST11 and ST16 in South America

Emergence of KPC-113 and KPC-114 variants in ceftazidime-avibactam-resistant Klebsiella pneumoniae belonging to high-risk clones ST11 and ST16 in South America

The dilemma of antibiotic susceptibility and clinical decision-making in a multi-drug-resistant Pseudomonas aeruginosa bloodstream infection

The balance between antibiotic resistance and fitness/virulence in Pseudomonas aeruginosa: an update on basic knowledge and fundamental research

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