Susceptibility of Imipenem-Susceptible but Meropenem-Resistant
            <i>bla</i>
            <sub>IMP-6</sub>
            -Carrying Enterobacteriaceae to Various Antibacterials, Including the Siderophore Cephalosporin Cefiderocol

Kanazawa, Sachi; Sato, Takafumi; Kohira, Naoki; Ito-Horiyama, Tsukasa; Tsuji, Masakatsu; Yamano, Yoshinori

doi:10.1128/aac.00576-17

Cited by 16 publications

(12 citation statements)

References 12 publications

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“…Cefiderocol is a new siderophore cephalosporin that is active against MDR Gramnegative organisms, including carbapenemase-producing Enterobacteriaceae (370)(371)(372)(373)(374)(375). At a dose of 2 g every 8 h, it reaches Ͼ50% time above the MIC for MICs of up to 8 mg/liter (376).…”

Section: Pipeline Of Drugs Against Crementioning

confidence: 99%

Treatment of Infections Caused by Extended-Spectrum-Beta-Lactamase-, AmpC-, and Carbapenemase-Producing Enterobacteriaceae

et al. 2018

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Therapy of invasive infections due to multidrug-resistant (MDR-E) is challenging, and some of the few active drugs are not available in many countries. For extended-spectrum β-lactamase and AmpC producers, carbapenems are the drugs of choice, but alternatives are needed because the rate of carbapenem resistance is rising. Potential active drugs include classic and newer β-lactam-β-lactamase inhibitor combinations, cephamycins, temocillin, aminoglycosides, tigecycline, fosfomycin, and, rarely, fluoroquinolones or trimethoprim-sulfamethoxazole. These drugs might be considered in some specific situations. AmpC producers are resistant to cephamycins, but cefepime is an option. In the case of carbapenemase-producing (CPE), only some "second-line" drugs, such as polymyxins, tigecycline, aminoglycosides, and fosfomycin, may be active; double carbapenems can also be considered in specific situations. Combination therapy is associated with better outcomes for high-risk patients, such as those in septic shock or with pneumonia. Ceftazidime-avibactam was recently approved and is active against KPC and OXA-48 producers; the available experience is scarce but promising, although development of resistance is a concern. New drugs active against some CPE isolates are in different stages of development, including meropenem-vaborbactam, imipenem-relebactam, plazomicin, cefiderocol, eravacycline, and aztreonam-avibactam. Overall, therapy of MDR-E infection must be individualized according to the susceptibility profile, type, and severity of infection and the features of the patient.

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Section: Pipeline Of Drugs Against Crementioning

confidence: 99%

Treatment of Infections Caused by Extended-Spectrum-Beta-Lactamase-, AmpC-, and Carbapenemase-Producing Enterobacteriaceae

et al. 2018

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“…IMP-1 Ser262 is replaced with glycine in these variants, and Enterobacteriaceae encoding IMP-6 frequently show susceptibility to imipenem. This feature caused the spread of bla IMP-6 -harboring plasmids in Japan as determined after screening the antibiotic susceptibility of infectious bacteria to imipenem as a representative carbapenem (5–7). Here, we report a novel variant, IMP-68, which is a point mutant of IMP-11 corresponding to the Ser262Gly substitution.…”

Section: Observationmentioning

confidence: 99%

IMP-68, a Novel IMP-Type Metallo-β-Lactamase in Imipenem-Susceptible Klebsiella pneumoniae

Kubota

Suzuki

Okuno

et al. 2019

mSphere

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IMP-type metallo-β-lactamases comprise one group of the “Big 5” carbapenemases. Here, a novel blaIMP-68 gene encoding IMP-68 (harboring a Ser262Gly point mutant of IMP-11) was discovered from meropenem-resistant but imipenem-susceptible Klebsiella pneumoniae TA6363. The Ser262Gly substitution was previously identified as important for substrate specificity according to a study of other IMP variants, including IMP-6. We confirmed that IMP-68 exhibited weaker imipenem-hydrolyzing activity than that for other carbapenems, demonstrating that the antimicrobial susceptibility profile of TA6363 originated from IMP-68 substrate specificity, with this likely to affect treatment strategies using antibacterial agents in clinical settings. Notably, the carbapenem resistance conferred by IMP-68 was undetectable based on the MIC of imipenem as a carbapenem representative, which demonstrates a comparable antimicrobial susceptibility profile to IMP-6-producing Enterobacteriaceae that previously spread in Japan due to lack of awareness of its existence.

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“…Mutations causing alteration or loss of porin channels, such as in OmpK35-36 in K. pneumoniae, do not appear to significantly impact the in vitro activity of cefiderocol [11,16,17]. Additionally, P. aeruginosa PAO1 strains with a transposon insertion in oprD leading to porin loss demonstrated only a twofold increase in cefiderocol MIC (0.25 lg/mL) over the parent strain compared to an eightfold increase in imipenem MIC (8 lg/mL).…”

mentioning

confidence: 95%

“…Steady-state kinetics demonstrated 3-10 times lower hydrolysis velocity of cefiderocol with NDM-1 compared to meropenem, ceftazidime and cefepime [16]. Cefiderocol has also demonstrated low-level hydrolysis by the IMP-type metallo-carbapenemases, IMP-1 and IMP-6, the latter of which can confer imipenem-susceptible, meropenem-resistant phenotypes to Enterobacterales strains [17]. Against Ambler class-D carbapenemases, OXA-48, OXA-23, and OXA-40, cefiderocol maintained full susceptibility with no changes to the MIC compared to aminopenicillins and carboxypenicillins that demonstrated highlevel resistance, and imipenem that demonstrated intermediate-level resistance in E. coli isolates modified with bla OXA-48 , bla OXA-23 and bla OXA-40 genes [18].…”

mentioning

confidence: 99%

Cefiderocol: A Novel Agent for the Management of Multidrug-Resistant Gram-Negative Organisms

2020

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Cefiderocol, formerly S-649266, is a first in its class, an injectable siderophore cephalosporin that combines a catechol-type siderophore and cephalosporin core with side chains similar to cefepime and ceftazidime. This structure and its unique mechanism of action confer enhanced stability against hydrolysis by many b-lactamases, including extended spectrum b-lactamases such as CTX-M, and carbapenemases such as KPC, NDM, VIM, IMP, OXA-23, OXA-48-like, OXA-51-like and OXA-58. Cefiderocol's spectrum of activity encompasses both lactosefermenting and non-fermenting Gram-negative pathogens, including carbapenem-resistant Enterobacterales. Cefiderocol recently received US Food and Drug Administration approval for the treatment of complicated urinary tract infections, including pyelonephritis, and is currently being evaluated in phase III trials for nosocomial pneumonia and infections caused by carbapenem-resistant Gram-negative pathogens. The purpose of this article is to review existing data on the mechanism of action, microbiology, pharmacokinetics, pharmacodynamics, efficacy, and safety of cefiderocol to assist clinicians in determining its place in therapy.

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Susceptibility of Imipenem-Susceptible but Meropenem-Resistant bla _IMP-6 -Carrying Enterobacteriaceae to Various Antibacterials, Including the Siderophore Cephalosporin Cefiderocol

Cited by 16 publications

References 12 publications

Treatment of Infections Caused by Extended-Spectrum-Beta-Lactamase-, AmpC-, and Carbapenemase-Producing Enterobacteriaceae

Treatment of Infections Caused by Extended-Spectrum-Beta-Lactamase-, AmpC-, and Carbapenemase-Producing Enterobacteriaceae

IMP-68, a Novel IMP-Type Metallo-β-Lactamase in Imipenem-Susceptible Klebsiella pneumoniae

Cefiderocol: A Novel Agent for the Management of Multidrug-Resistant Gram-Negative Organisms

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Susceptibility of Imipenem-Susceptible but Meropenem-Resistant bla IMP-6 -Carrying Enterobacteriaceae to Various Antibacterials, Including the Siderophore Cephalosporin Cefiderocol

Cited by 16 publications

References 12 publications

Treatment of Infections Caused by Extended-Spectrum-Beta-Lactamase-, AmpC-, and Carbapenemase-Producing Enterobacteriaceae

Treatment of Infections Caused by Extended-Spectrum-Beta-Lactamase-, AmpC-, and Carbapenemase-Producing Enterobacteriaceae

IMP-68, a Novel IMP-Type Metallo-β-Lactamase in Imipenem-Susceptible Klebsiella pneumoniae

Cefiderocol: A Novel Agent for the Management of Multidrug-Resistant Gram-Negative Organisms

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Susceptibility of Imipenem-Susceptible but Meropenem-Resistant bla _IMP-6 -Carrying Enterobacteriaceae to Various Antibacterials, Including the Siderophore Cephalosporin Cefiderocol