Use of carbapenems in the combined treatment of emerging ceftazidime/avibactam-resistant and carbapenem-susceptible KPC-producing Klebsiella pneumoniae infections: Report of a case and review of the literature

Cano, Ángela; Guzmán-Puche, Julia; García-Gutiérrez, Manuel; Castón, Juan José; Gracia-Ahufinger, Irene; Pérez‐Nadales, Elena; Recio, Manuel; Natera, Alejandra M.; Marfil-Pérez, Eduardo; Martı́nez-Martı́nez, Luis; Torre‐Cisneros, Julián

doi:10.1016/j.jgar.2019.11.007

Cited by 39 publications

(23 citation statements)

References 12 publications

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“…To date, a total of 88 bla KPC gene subtypes have been published, the detection of which has presented an uptrend since 2015 and has shown blowout growth since 2020, and 52.3% of them (46/88) were released after 2020. Based on previous reports and data from GenBank database ( https://www.ncbi.nlm.nih.gov/pathogens/refgene/#gene_family :(blaKPC), by August 16, 2021), bla KPC gene subtypes mediating inhibitor resistance have successively emerged by 2016 and are now mainly reported in Europe, China, and the United States ( 18 – 20 ). Especially in the recent 3 years, 53.8%(28/52) novel bla KPC gene subtypes are resistant to inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Multiple Novel Ceftazidime-Avibactam-Resistant Variants of bla _KPC-2 -Positive Klebsiella pneumoniae in Two Patients

et al. 2022

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Carbapenem-resistant K. pneumoniae which was classified as the most urgent threat by World Health Organization, is the most critical public health concern due to its high mortality rate. Recently, the rapid mutation of bla KPC has occurred during anti-infective therapy, which posed an unexpected challenge for both the diagnostic laboratory and clinical practice.

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Section: Discussionmentioning

confidence: 99%

Multiple Novel Ceftazidime-Avibactam-Resistant Variants of bla _KPC-2 -Positive Klebsiella pneumoniae in Two Patients

et al. 2022

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“…Indeed, KPC-Kp isolates with mutations in the -loop of the bla KPC gene have previously been observed to revert to a carbapenem-resistant phenotype in vitro (Shields et al, 2017c). Some case reports have been published showing variable success of using carbapenems to treat patients with CAZ/AVIresistant, MERO-susceptible KPC-Kp (Cano et al, 2019). Unlike MERO monotherapy, the combination of CAZ/AVI and MERO may act synergistically to prevent the reversion to carbapenem resistance.…”

Section: Discussionmentioning

confidence: 99%

In vitro Optimization of Ceftazidime/Avibactam for KPC-Producing Klebsiella pneumoniae

Huang

Perez

et al. 2021

Front. Microbiol.

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Ceftazidime/avibactam is an important treatment option for infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp), however, resistance can emerge during treatment. The objective of the study was to define the ceftazidime/avibactam concentrations required to suppress bacterial regrowth in ceftazidime/avibactam susceptible isolates and identify active therapies against ceftazidime/avibactam-resistant KPC-Kp. Time-kill assays were performed against twelve ST258 KPC-Kp isolates that harbored blaKPC–2 or blaKPC–3. Nine KPC-Kp isolates (KPC-Kp 5A, 6A, 7A, 8A, 9A, 24A, 25A, 26A, and 27A) were susceptible to ceftazidime/avibactam, two (KPC-Kp 6B and 7B) were ceftazidime/avibactam resistant and meropenem susceptible, and one (KPC-Kp 1244) was resistant to both ceftazidime/avibactam and meropenem. Sequencing of the blaKPC genes revealed mutations in KPC-Kp 6B (D179Y substitution) and 7B (novel 21 base pair deletion) that both affected the Ω-loop encoding portion of the gene. Time-kill assays showed that against ceftazidime/avibactam-susceptible KPC-Kp, ceftazidime/avibactam concentrations ≥40/7.5 mg/L caused mean 5.42 log10CFU/mL killing and suppressed regrowth. However, regrowth occurred for some KPC-Kp isolates with a ceftazidime/avibactam concentration of 20/3.75 mg/L. Against ceftazidime/avibactam-resistant and meropenem-susceptible KPC-Kp 6B and 7B, bactericidal activity and synergy was observed for ceftazidime/avibactam in combination with meropenem ≤3.125 mg/L, while meropenem concentrations ≥50 mg/L were bactericidal as monotherapy. In contrast, clinically achievable concentrations of ceftazidime/avibactam were bactericidal against KPC-Kp 1244, which was ceftazidime/avibactam-resistant and meropenem-resistant due to outer membrane porin mutations and elevated blaKPC expression. Achieving high ceftazidime/avibactam concentrations may help to suppress bacterial regrowth in the presence of ceftazidime/avibactam. The optimal treatment approach for ceftazidime/avibactam-resistant KPC-Kp likely depends on the mechanism of resistance. Additional studies are warranted to confirm these findings.

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“…Shields et al first reported the evolution of CZA resistance during the treatment of K. pneumoniae infections in three patients from the United States in 2016 [ 3 ]. The treatment-emergent CZA resistance was subsequently described in Greece [ 27 ], Italy [ 9 , 15 , 16 ], Finland [ 10 ], Germany [ 12 ], and Spain [ 28 ] since then. And we recently reported four CZA-resistant KPC-KP recovered from lung transplant recipients after 13–22 days of CZA treatment in China [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

“…KPC-31 [ 4 ] and KPC-33 [ 6 ] were the first two reported mechanisms associated with CZA resistance during treatment. Besides, KPC-35 [ 8 ], KPC-36 [ 15 ], KPC-41 [ 14 ], KPC-44 [ 10 ], KPC-48 [ 28 ], and KPC-57 [ 27 ] were also reported to be associated with acquired CZA resistance. We showed that CZA resistance in our 4 CZA-resistant isolates is due to mutations of bla KPC , and that two novel KPC variants (KPC-51, KPC-52) are also associated with CZA resistance [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Increased gene expression and copy number of mutated blaKPC lead to high-level ceftazidime/avibactam resistance in Klebsiella pneumoniae

Sun

Wang

et al. 2021

BMC Microbiol

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Background Resistance to ceftazidime-avibactam was reported, and it is important to investigate the mechanisms of ceftazidime/avibactam resistance in K. pneumoniae with mutations in blaKPC. Results We report the mutated blaKPC is not the only mechanism related to CZA resistance, and investigate the role of outer porin defects, efflux pump, and relative gene expression and copy number of blaKPC and ompk35/36. Four ceftazidime/avibactam-sensitive isolates detected wild type blaKPC-2, while 4 ceftazidime/avibactam-resistant isolates detected mutated blaKPC (blaKPC-51, blaKPC-52, and blaKPC-33). Compared with other ceftazidime/avibactam-resistant isolates with the minimal inhibitory concentration of ceftazidime/avibactam ranging 128–256 mg/L, the relative gene expression and copy number of blaKPC was increased in the isolate which carried blaKPC-51 and also showed the highest minimal inhibitory concentration of ceftazidime/avibactam at 2048 mg/L. The truncated Ompk35 contributes rare to ceftazidime/avibactam resistance in our isolates. No significant difference in minimal inhibitory concentration of ceftazidime/avibactam was observed after the addition of PABN. Conclusions Increased gene expression and copy number of mutated blaKPC can cause high-level ceftazidime/avibactam resistance.

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Use of carbapenems in the combined treatment of emerging ceftazidime/avibactam-resistant and carbapenem-susceptible KPC-producing Klebsiella pneumoniae infections: Report of a case and review of the literature

Cited by 39 publications

References 12 publications

Multiple Novel Ceftazidime-Avibactam-Resistant Variants of bla _KPC-2 -Positive Klebsiella pneumoniae in Two Patients

Multiple Novel Ceftazidime-Avibactam-Resistant Variants of bla _KPC-2 -Positive Klebsiella pneumoniae in Two Patients

In vitro Optimization of Ceftazidime/Avibactam for KPC-Producing Klebsiella pneumoniae

Increased gene expression and copy number of mutated blaKPC lead to high-level ceftazidime/avibactam resistance in Klebsiella pneumoniae

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Use of carbapenems in the combined treatment of emerging ceftazidime/avibactam-resistant and carbapenem-susceptible KPC-producing Klebsiella pneumoniae infections: Report of a case and review of the literature

Cited by 39 publications

References 12 publications

Multiple Novel Ceftazidime-Avibactam-Resistant Variants of bla KPC-2 -Positive Klebsiella pneumoniae in Two Patients

Multiple Novel Ceftazidime-Avibactam-Resistant Variants of bla KPC-2 -Positive Klebsiella pneumoniae in Two Patients

In vitro Optimization of Ceftazidime/Avibactam for KPC-Producing Klebsiella pneumoniae

Increased gene expression and copy number of mutated blaKPC lead to high-level ceftazidime/avibactam resistance in Klebsiella pneumoniae

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Multiple Novel Ceftazidime-Avibactam-Resistant Variants of bla _KPC-2 -Positive Klebsiella pneumoniae in Two Patients

Multiple Novel Ceftazidime-Avibactam-Resistant Variants of bla _KPC-2 -Positive Klebsiella pneumoniae in Two Patients