A Whole-Genome Sequencing-Based Approach for the Characterization of Klebsiella pneumoniae Co-Producing KPC and OXA-48-like Carbapenemases Circulating in Sardinia, Italy

Del Rio, Arcadia; Fox, Valeria; Muresu, Narcisa; Sechi, Illari; Cossu, Andrea; Palmieri, Alessandra; Scutari, Rossana; Alteri, Claudia; Sotgiu, Giovanni; Castiglia, Paolo; Piana, Andrea

doi:10.3390/microorganisms11092354

Cited by 3 publications

(2 citation statements)

References 60 publications

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“…The emergence of CRKP is primarily from the different types of carbapenemase production ( K. pneumoniae carbapenemases (KPC), New Delhi metallo-β-lactamase (NDM), Verona integron-encoded metallo-β-lactamase (VIM), imipenemase metallo-β-lactamase (IMP), and oxacillinase-48-type carbapenemases (OXA-48)), which further reduce the therapeutic option and increase the mortality risk. [ 3 , 12 , 14 , 15 ]. Furthermore, efflux pump overexpression, decreased outer membrane protein permeability, and beta-lactamase production are all important mechanisms for CRKP strain formation [ 1 , 3 ].…”

Section: Discussionmentioning

confidence: 99%

Risk Factors and Outcomes of Community-Acquired Carbapenem-Resistant Klebsiella pneumoniae Infection in Elderly Patients

Chen,

Tsai,

Lai

et al. 2024

Antibiotics

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The increasing prevalence of carbapenem-resistant Klebsiella pneumoniae (CRKP) infections is a global concern. Elderly patients have a diminished immune response and functional reserve, and are thus more vulnerable to bacterial infection. This study aimed to investigate the risk factors and outcomes in elderly patients with community-acquired CRKP infections. We performed a retrospective cohort study in a tertiary medical center between 1 January 2021, and 31 December 2021. All elderly patients who visited the emergency department during this period with culture-positive K. pneumoniae were enrolled, and their baseline demographics, laboratory profiles, management strategies, and outcomes were recorded and analyzed. We identified 528 elderly patients with K. pneumonia infection, and the proportion of patients with CRKP infection was 10.2% (54/528). Recent intensive care unit (ICU) admission and prior carbapenem use are independent risk factors for CRKP infection in elderly patients. Compared to patients with carbapenem-sensitive K. pneumoniae infection, those with CRKP infection had a significantly higher risk of adverse outcomes, including ICU care, respiratory failure, septic shock, and 90-day mortality. CRKP infection was also identified as an independent risk factor for 90-day mortality. Clinicians should be aware of the increasing prevalence of CRKP infections in elderly patients and judiciously choose appropriate antibiotics for these patients.

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Section: Discussionmentioning

confidence: 99%

Risk Factors and Outcomes of Community-Acquired Carbapenem-Resistant Klebsiella pneumoniae Infection in Elderly Patients

Chen,

Tsai,

Lai

et al. 2024

Antibiotics

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“…Most of these mutants showed high-level resistance to ceftazidime-avibactam, such as bla KPC-31 [ 27 ], bla KPC-33 [ 20 ], etc. Moreover, the increased bla KPC expression, membrane porin deficiency and the co-production of KPC variants and other carbapenemases could mediate both carbapenem and ceftazidime-avibactam resistance [ 44 , 45 ]. The emergence of these KPC mutants with high evolutionary potential posed a challenge to the anti-infective therapy.…”

Section: Discussionmentioning

confidence: 99%

In vitro mimicry of in vivo KPC mutations by ceftazidime-avibactam: phenotypes, mechanisms, genetic structure and kinetics of enzymatic hydrolysis

Shen,

Tang,

Yang

et al. 2024

Emerging Microbes & Infections

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Ceftazidime-avibactam (CZA) is employed for the treatment of infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-KP). Resistance to CZA is frequently linked to point mutations in the bla KPC . We conducted in vitro simulations of in vivo bla KPC mutations using CZA. Four pre-therapy KPC-KP isolates (K1, K2, K3, and K4) were evaluated, all initially exhibited susceptibility to CZA and produced KPC-2. The crucial distinction was that following CZA treatment, the bla KPC-2 mutated in K1, K2, and K3, rendering them resistant to CZA, while K4 achieved microbiological clearance, and bla KPC-2 remained unaltered. The induction assay identified various bla KPC-2 variants, including bla KPC-25 , bla KPC-127 , bla KPC-100 , bla KPC-128 , bla KPC-137 , bla KPC-138 , bla KPC-144 and bla KPC-180 . Our findings suggest that the resistance of KPC-KP to CZA primarily results from the emergence of KPC variants, complemented by increased bla KPC expression. A close correlation exists between avibactam concentration and the rate of increased CZA minimum Inhibitory concentration, as well as bla KPC mutation. Inadequate avibactam concentration is more likely to induce resistance in strains against CZA, there is also a higher likelihood of mutation in the bla KPC-2 and the optimal avibactam ratio remains to be determined. Simultaneously, we selected a bla KPC-33 -producing K. pneumoniae strain (mutated from bla KPC-2 ) and induced it with imipenem and meropenem, respectively. The bla KPC-2 was detected during the process, indicating that the mutation is reversible. Clinical use of carbapenems to treat KPC variant strains increases the risk of infection, as the gene can mutate back to bla KPC-2 , rendering the strain even more cross-resistant to carbapenems and CZA.

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The contribution of porins to enterobacterial drug resistance

Davin-Regli,

Pagès,

Vergalli

2024

Journal of Antimicrobial Chemotherapy

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In Enterobacteriaceae, susceptibility to cephalosporins and carbapenems is often associated with membrane and enzymatic barrier resistance. For about 20 years, a large number of Klebsiella pneumoniae, Escherichia coli and Enterobacter cloacae presenting ß-lactam resistance have been isolated from medical clinics. In addition, some of the resistant isolates exhibited alterations in the outer membrane porin OmpC-OmpF orthologues, resulting in the complete absence of gene expression, replacement by another porin or mutations affecting channel properties. Interestingly, for mutations reported in OmpC-OmpF orthologues, major changes in pore function were found to be present in the gene encoding for OmpC. The alterations were located in the constriction region of the porin and the resulting amino acid substitutions were found to induce severe restriction of the lumen diameter and/or alteration of the electrostatic field that governs the diffusion of charged molecules. This functional adaptation through porins maintains the entry of solutes necessary for bacterial growth but critically controls the influx of harmful molecules such as β-lactams at a reduced cost. The data recently published show the importance of understanding the underlying parameters affecting the uptake of antibiotics by infectious bacteria. Furthermore, the development of reliable methods to measure the concentration of antibiotics within bacterial cells is key to combat impermeability-resistance mechanisms.

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A Whole-Genome Sequencing-Based Approach for the Characterization of Klebsiella pneumoniae Co-Producing KPC and OXA-48-like Carbapenemases Circulating in Sardinia, Italy

Cited by 3 publications

References 60 publications

Risk Factors and Outcomes of Community-Acquired Carbapenem-Resistant Klebsiella pneumoniae Infection in Elderly Patients

Risk Factors and Outcomes of Community-Acquired Carbapenem-Resistant Klebsiella pneumoniae Infection in Elderly Patients

In vitro mimicry of in vivo KPC mutations by ceftazidime-avibactam: phenotypes, mechanisms, genetic structure and kinetics of enzymatic hydrolysis

The contribution of porins to enterobacterial drug resistance

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