Cefiderocol activity is compromised by acquired extended-spectrum oxacillinases in Pseudomonas aeruginosa

Vuillemin, Xavier; Silva, Maëlle Da; Bour, Maxime; Landon, C.; Plésiat, Patrick; Jeannot, Katy

doi:10.1016/j.ijantimicag.2023.106917

Cited by 5 publications

(2 citation statements)

References 23 publications

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“…This may be explained by the fact that cefepime is particularly affected by the overexproduction of efflux pumps such as MexAB-OprM, or MexXY. In addition, we did not analyze the presence or absence of bla OXA-like in our P. aeruginosa isolate collection, and it may be that zidebactam and taniborbactam are not efficient β-lactamase inhibitors against OXA-2- or OXA-10-type β-lactamases, which are known to be widely distributed in P. aeruginosa and contributing to the reduced susceptibility to cefiderocol [ 11 , 19 ]. Finally, zidebactam and nacubactam have a lower intrinsic antibacterial activity against P. aeruginosa in comparison to Enterobacterales, considering that the MIC values are approximately around 4–16 mg/L for zidebactam, and above 32 mg/L for nacubactam for Pseudomonas spp.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, several mechanisms of resistance to cefiderocol have been recently reported, such as porin mutations, mutations affecting siderophore receptors, efflux pump overproduction, and modifications of the target (penicillin binding protein 3, or PBP-3), or production of some given β-lactamases [ 8 ]. A wide range of β-lactamases including class A (PER, BEL, SHV, KPC), class B (NDM, VIM), class C (AmpC), or class D β-lactamases (OXA-2, OXA-10, OXA-46) has been demonstrated to contribute to reduce the susceptibility to cefiderocol [ 8 – 11 ]. In addition, the progressive in vivo development of reduced susceptibility to cefiderocol has been reported in clinical contexts, particularly within two clinical trials [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

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Multidrug-resistant Gram-negative clinical isolates with reduced susceptibility/resistance to cefiderocol: which are the best present and future therapeutic alternatives?

Le Terrier,

Freire,

Nordmann

et al. 2023

Eur J Clin Microbiol Infect Dis

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Purpose To evaluate the different present and future therapeutic β-lactam/β-lactamase inhibitor (BL/BLI) alternatives, namely aztreonam-avibactam, imipenem-relebactam, meropenem-vaborbactam, cefepime-zidebactam, cefepime-taniborbactam, meropenem-nacubactam, and sulbactam-durlobactam against clinical isolates showing reduced susceptibility or resistance to cefiderocol in Enterobacterales, Acinetobacter baumannii, and Pseudomonas aeruginosa. Methods MIC values of aztreonam, aztreonam-avibactam, cefepime, cefepime-taniborbactam, cefepime-zidebactam, imipenem, imipenem-relebactam, meropenem, meropenem-vaborbactam, meropenem-nacubactam, sulbactam-durlobactam, and cefiderocol combined with a BLI were determined for 67, 9, and 11 clinical Enterobacterales, P. aeruginosa or A. baumannii isolates, respectively, showing MIC values of cefiderocol being ≥1 mg/L. If unavailable, the respective β-lactam breakpoints according to EUCAST were used for BL/BLI combinations. Results For Enterobacterales, the susceptibility rates for aztreonam, cefepime, imipenem, and meropenem were 7.5%, 0%, 10.4%, and 10.4%, respectively, while they were much higher for cefepime-zidebactam (91%), cefiderocol-zidebactam (91%), meropenem-nacubactam (71.6%), cefiderocol-nacubactam (74.6%), and cefiderocol-taniborbactam (76.1%), as expected. For P. aeruginosa isolates, the higher susceptibility rates were observed for imipenem-relebactam, cefiderocol-zidebactam, and meropenem-vaborbactam (56% for all combinations). For A. baumannii isolates, lower susceptibility rates were observed with commercially or under development BL/BLI combos; however, a high susceptibility rate (70%) was found for sulbactam-durlobactam and when cefiderocol was associated to some BLIs. Conclusions Zidebactam- and nacubactam-containing combinations showed a significant in vitro activity against multidrug-resistant Enterobacterales clinical isolates with reduced susceptibility to cefiderocol. On the other hand, imipenem-relebactam and meropenem-vaborbactam showed the highest susceptibility rates against P. aeruginosa isolates. Finally, sulbactam-durlobactam and cefiderocol combined with a BLI were the only effective options against A. baumannii tested isolates.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Multidrug-resistant Gram-negative clinical isolates with reduced susceptibility/resistance to cefiderocol: which are the best present and future therapeutic alternatives?

Le Terrier,

Freire,

Nordmann

et al. 2023

Eur J Clin Microbiol Infect Dis

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Extreme resistance to the novel siderophore-cephalosporin cefiderocol in an extensively drug-resistant Klebsiella pneumoniae strain causing fatal pneumonia with sepsis: genomic analysis and synergistic combinations for resistance reversal

Daoud,

Allam,

Collyns

et al. 2023

Eur J Clin Microbiol Infect Dis

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Impact of chromosomally encoded resistance mechanisms and transferable β-lactamases on the activity of cefiderocol and innovative β-lactam/β-lactamase inhibitor combinations against Pseudomonas aeruginosa

González-Pinto,

Alonso-García,

Blanco-Martín

et al. 2024

Journal of Antimicrobial Chemotherapy

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Objectives We aimed to compare the stability of the newly developed β-lactams (cefiderocol) and β-lactam/β-lactamase inhibitor combinations (ceftazidime/avibactam, ceftolozane/tazobactam, aztreonam/avibactam, cefepime/taniborbactam, cefepime/zidebactam, imipenem/relebactam, meropenem/vaborbactam, meropenem/nacubactam and meropenem/xeruborbactam) against the most clinically relevant mechanisms of mutational and transferable β-lactam resistance in Pseudomonas aeruginosa. Methods We screened a collection of 61 P. aeruginosa PAO1 derivatives. Eighteen isolates displayed the most relevant mechanisms of mutational resistance to β-lactams. The other 43 constructs expressed transferable β-lactamases from genes cloned in pUCP-24. MICs were determined by reference broth microdilution. Results Cefiderocol and imipenem/relebactam exhibited excellent in vitro activity against all of the mutational resistance mechanisms studied. Aztreonam/avibactam, cefepime/taniborbactam, cefepime/zidebactam, meropenem/vaborbactam, meropenem/nacubactam and meropenem/xeruborbactam proved to be more vulnerable to mutational events, especially to overexpression of efflux operons. The agents exhibiting the widest spectrum of activity against transferable β-lactamases were aztreonam/avibactam and cefepime/zidebactam, followed by cefepime/taniborbactam, cefiderocol, meropenem/xeruborbactam and meropenem/nacubactam. However, some MBLs, particularly NDM enzymes, may affect their activity. Combined production of certain enzymes (e.g. NDM-1) with increased MexAB-OprM-mediated efflux and OprD deficiency results in resistance to almost all agents tested, including last options such as aztreonam/avibactam and cefiderocol. Conclusions Cefiderocol and new β-lactam/β-lactamase inhibitor combinations show promising and complementary in vitro activity against mutational and transferable P. aeruginosa β-lactam resistance. However, the combined effects of efflux pumps, OprD deficiency and efficient β-lactamases could still result in the loss of all therapeutic options. Resistance surveillance, judicious use of new agents and continued drug development efforts are encouraged.

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Cefiderocol activity is compromised by acquired extended-spectrum oxacillinases in Pseudomonas aeruginosa

Cited by 5 publications

References 23 publications

Multidrug-resistant Gram-negative clinical isolates with reduced susceptibility/resistance to cefiderocol: which are the best present and future therapeutic alternatives?

Multidrug-resistant Gram-negative clinical isolates with reduced susceptibility/resistance to cefiderocol: which are the best present and future therapeutic alternatives?

Extreme resistance to the novel siderophore-cephalosporin cefiderocol in an extensively drug-resistant Klebsiella pneumoniae strain causing fatal pneumonia with sepsis: genomic analysis and synergistic combinations for resistance reversal

Impact of chromosomally encoded resistance mechanisms and transferable β-lactamases on the activity of cefiderocol and innovative β-lactam/β-lactamase inhibitor combinations against Pseudomonas aeruginosa

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