In vitro activity of the novel siderophore cephalosporin, cefiderocol, in Gram-negative pathogens in Europe by site of infection

Candel, Francisco Javier; Henriksen, Anne Santerre; Longshaw, Christopher; Yamano, Yoshinori; Oliver, Antonio

doi:10.1016/j.cmi.2021.07.018

Cited by 34 publications

(33 citation statements)

References 25 publications

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“…Thirty-eight studies reporting on the in vitro activity of cefiderocol against Gram-negative bacteria were included ( Ito et al, 2015 ; Ito et al, 2016 ; Kohira et al, 2015 ; Falagas et al, 2017 ; Dobias et al, 2017 ; Hackel et al, 2017 ; Kanazawa et al, 2017 ; Yamano et al, 2017 ; Hackel et al, 2018 ; Ito et al, 2018a ; Jacobs et al, 2018 ; Karlowsky et al, 2019 ; Kazmierczak et al, 2019 ; Hsueh et al, 2019 ; Iregui et al, 2019 ; Albano et al, 2020 ; Biagi et al, 2020 ; Delgado-Valverde et al, 2020 ; Golden et al, 2020 ; Johnston et al, 2020 ; Kresken et al, 2020 ; Longshaw et al, 2020 ; Morris et al, 2020 ; Mushtaq et al, 2020 ; Rolston et al, 2020 ; Trebosc et al, 2020 ; Abdul-Mutakabbir et al, 2021 ; Bhagwat et al, 2021 ; Bianco et al, 2021 ; Burnard et al, 2021 ; Cercenado et al, 2021 ; Gant et al, 2021 ; Candel et al, 2022 ; Johnston et al, 2021 ; Lee et al, 2021 ; Liu et al, 2021 ; Stracquadanio et al, 2021 ; Zalacain et al, 2021 ). A total of 53,416 isolates, including 34,805 Enterobacterales , 8297 P. aeruginosa , 7249 Acinetobacter spp , 2508 Stenotrophomonas maltophilia and 549 Burkholderia spp , mainly collected from North America, Europe and East Asia excluding Chinese mainland, were tested for cefiderocol susceptibility.…”

Section: Resultsmentioning

confidence: 99%

Cefiderocol for the Treatment of Multidrug-Resistant Gram-Negative Bacteria: A Systematic Review of Currently Available Evidence

et al. 2022

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Cefiderocol is a novel synthetic siderophore-conjugated antibiotic that hijacks the bacterial iron transport systems facilitating drug entry into cells, achieving high periplasmic concentrations. This systematic review analyzed the currently available literature on cefiderocol. It summarized in vitro susceptibility data, in vivo antimicrobial activity, pharmacokinetics/pharmacodynamics (PK/PD), clinical efficacy, safety and resistance mechanisms of cefiderocol. Cefiderocol has potent in vitro and in vivo activity against multidrug-resistant (MDR) Gram-negative bacteria, including carbapenem-resistant isolates. But New Delhi Metallo-β-lactamase (NDM)- positive isolates showed significantly higher MICs than other carbapenemase-producing Enterobacterales, with a susceptible rate of 83.4% for cefiderocol. Cefiderocol is well-tolerated, and the PK/PD target values can be achieved using a standard dose regimen or adjusted doses according to renal function. Clinical trials demonstrated that cefiderocol was non-inferiority to the comparator drugs in treating complicated urinary tract infection and nosocomial pneumonia. Case reports and series showed that cefiderocol was a promising therapeutic agent in carbapenem-resistant infections. However, resistant isolates and reduced susceptibility during treatment to cefiderocol have already been reported. In conclusion, cefiderocol is a promising powerful weapon for treating MDR recalcitrant infections.

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Section: Resultsmentioning

confidence: 99%

Cefiderocol for the Treatment of Multidrug-Resistant Gram-Negative Bacteria: A Systematic Review of Currently Available Evidence

et al. 2022

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“…Considering the results of studies of isogenic strains, each of the mechanisms described above appears to be insufficient to raise, on its own, cefiderocol MICs above current PK/PD breakpoints [ 29 , 31 , 40 , 46 , 47 , 50 , 51 , 54 , 55 ]. Indeed, the majority of strains harbouring various mechanisms of resistance, including various β-lactamases, remain susceptible to cefiderocol [ 8 , 9 , 10 , 11 , 12 , 47 ]. This suggests that a combination of different mechanisms is necessary, including coexpression of different β-lactamases, mutations affecting siderophore–drug receptors expression/function, mutations affecting porin expression/function, overexpression of efflux pumps, and target (PBP-3) modification [ 37 , 59 , 64 ].…”

Section: Resultsmentioning

confidence: 99%

“…Based on several prior studies, including large multinational cohorts [ 8 , 9 , 10 , 11 , 12 , 13 ], cefiderocol appears to be active against the majority of Enterobacterales, A. baumannii , P. aeruginosa , and S. maltophilia , including isolates that are resistant to carbapenems, ceftazidime/avibactam, ceftolozane/tazobactam, meropenem/vaborbactam, imipenem/relabactam, and polymyxins. Nevertheless, cefiderocol resistance has been reported to be high in selected cohorts [ 14 , 15 , 16 , 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

Cefiderocol: Systematic Review of Mechanisms of Resistance, Heteroresistance and In Vivo Emergence of Resistance

2022

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Cefiderocol appears promising, as it can overcome most β-lactam resistance mechanisms (including β-lactamases, porin mutations, and efflux pumps). Resistance is uncommon according to large multinational cohorts, including against isolates resistant to carbapenems, ceftazidime/avibactam, ceftolozane/tazobactam, and colistin. However, alarming proportions of resistance have been reported in some recent cohorts (up to 50%). A systematic review was conducted in PubMed and Scopus from inception to May 2022 to review mechanisms of resistance, prevalence of heteroresistance, and in vivo emergence of resistance to cefiderocol during treatment. A variety of mechanisms, typically acting in concert, have been reported to confer resistance to cefiderocol: β-lactamases (especially NDM, KPC and AmpC variants conferring resistance to ceftazidime/avibactam, OXA-427, and PER- and SHV-type ESBLs), porin mutations, and mutations affecting siderophore receptors, efflux pumps, and target (PBP-3) modifications. Coexpression of multiple β-lactamases, often in combination with permeability defects, appears to be the main mechanism of resistance. Heteroresistance is highly prevalent (especially in A. baumannii), but its clinical impact is unclear, considering that in vivo emergence of resistance appears to be low in clinical studies. Nevertheless, cases of in vivo emerging cefiderocol resistance are increasingly being reported. Continued surveillance of cefiderocol’s activity is important as this agent is introduced in clinical practice.

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“…Notably, the drop of activity between carbapenem-susceptible and CR strains of K. pneumoniae was deeper for CFDC (98.0% vs. 69.2%) respect to CZA (99.6% vs. 75%), while the opposite effect occurred for E. coli strains (CFDC 99.4% vs. 77.8%; CZA 99.7% vs. 33.3%). When considering infections by DTR- Pa , the difference was striking, with 97.5% susceptibility to CFDC vs. 44.1% to ceftolozane/tazobactam and 43.2% to CZA, respectively [ 60 ]. CFDC was also evaluated against a collection of 150 DTR- Ab and was found to be active on 94% of the colistin-resistant isolates [ 61 ].…”

Section: Resultsmentioning

confidence: 99%

“…At present, DTR- Ab is probably the pathogen with the most limited available treatment options. In vitro and early clinical evidence showed CFDC to be a promising and effective tool for Acinetobacter infections [ 60 , 73 , 74 ].…”

Section: Algorithm Constructionmentioning

confidence: 99%

Place in Therapy of the Newly Available Armamentarium for Multi-Drug-Resistant Gram-Negative Pathogens: Proposal of a Prescription Algorithm

et al. 2021

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The worldwide propagation of antimicrobial resistance represents one of the biggest threats to global health and development. Multi-drug-resistant organisms (MDROs), including carbapenem-resistant non-fermenting Gram-negatives and Enterobacterales, present a heterogeneous and mutating spread. Infections by MDRO are often associated with an unfavorable outcome, especially among critically ill populations. The polymyxins represented the backbone of antibiotic regimens for Gram-negative MDROs in recent decades, but their use presents multiple pitfalls. Luckily, new agents with potent activity against MDROs have become available in recent times and more are yet to come. Now, we have the duty to make the best use of these new therapeutic tools in order not to prematurely compromise their effectiveness and at the same time improve patients’ outcomes. We reviewed the current literature on ceftazidime/avibactam, meropenem/vaborbactam and cefiderocol, focusing on antimicrobial spectrum, on the prevalence and mechanisms of resistance development and on the main in vitro and clinical experiences available so far. Subsequently, we performed a step-by-step construction of a speculative algorithm for a reasoned prescription of these new antibiotics, contemplating both empirical and targeted use. Attention was specifically posed on patients with life-risk conditions and in settings with elevated prevalence of MDRO.

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In vitro activity of the novel siderophore cephalosporin, cefiderocol, in Gram-negative pathogens in Europe by site of infection

Cited by 34 publications

References 25 publications

Cefiderocol for the Treatment of Multidrug-Resistant Gram-Negative Bacteria: A Systematic Review of Currently Available Evidence

Cefiderocol for the Treatment of Multidrug-Resistant Gram-Negative Bacteria: A Systematic Review of Currently Available Evidence

Cefiderocol: Systematic Review of Mechanisms of Resistance, Heteroresistance and In Vivo Emergence of Resistance

Place in Therapy of the Newly Available Armamentarium for Multi-Drug-Resistant Gram-Negative Pathogens: Proposal of a Prescription Algorithm

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