Activity of the novel siderophore cephalosporin cefiderocol against multidrug-resistant Gram-negative pathogens

Dobiáš, J; Denervaud-Tendon, Valérie; Poirel, Laurent; Nordmann, Patrice

doi:10.1007/s10096-017-3063-z

Cited by 135 publications

(103 citation statements)

References 18 publications

(19 reference statements)

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“…In this study isolates with MIC values ≥2 mg/L were considered to have elevated cefiderocol MICs, yet few were identified in this collection ( n =13). This finding is expected, with previous in vitro studies identifying very few resistant isolates for several Gram-negative bacilli species, for example only 24/753 isolates showed MICs ≥8 mg/L from a global dataset 31 , 54/8954 isolates had MICs ≥4 mg/L 13 and no resistant isolates were identified among 189 isolates from Greece 32 . In vitro MIC 90 values of the 250 primary B. pseudomallei isolates was 1 mg/L in this study, higher than the previously described MIC 90 of 0.25 mg/L obtained from a pilot study of 30 B. pseudomallei isolates 14 .…”

Section: Discussionsupporting

confidence: 73%

Burkholderia pseudomalleiclinical isolates are highly susceptiblein vitroto cefiderocol, a novel siderophore cephalosporin

Burnard

Robertson

Henderson

et al. 2020

Preprint

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Cefiderocol is a novel cephalosporin designed to treat multidrug resistant Gram-negative infections. By forming a chelated complex with ferric iron, cefiderocol is transported into the periplasmic space via bacterial iron transport systems and primarily binds to penicillin-binding protein 3 (PBP3) to inhibit peptidoglycan synthesis. This mode of action results in cefiderocol having greater in vitro activity against many Gram-negative bacilli than currently used carbapenems, β-lactam/β-lactamase inhibitor combinations, and cephalosporins. Thus, we investigated the in vitro activity of cefiderocol (S-649266) against a total of 271 clinical isolates of Burkholderia pseudomallei from Australia. The collection was comprised of primary isolates (92.3%) and subsequent isolates (7.7%). Minimum inhibitory concentrations (MIC) of cefiderocol ranged from ≤0.03 to 32 mg/L, where the MIC90 was 1 mg/L and 16 mg/L for primary and subsequent isolates, respectively. Based upon non-species specific (Gram-negative bacilli) clinical breakpoints for cefiderocol (MIC ≤ 4 mg/L), twelve isolates (4.4%) would be classified as non-susceptible. Further testing for co-resistance to meropenem, ceftazidime, trimethoprim-sulfamethoxazole, amoxicillin-clavulanate and doxycycline was performed on a subset of isolates with elevated cefiderocol MICs (≥2 mg/L, 4.8%) and 84.6% of these isolates exhibited resistance to at least one of these antimicrobials. Cefiderocol was found to be highly active in vitro against B. pseudomallei primary clinical isolates. This novel compound shows great potential for the treatment of melioidosis in endemic countries and should be explored further.

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Section: Discussionsupporting

confidence: 73%

Burkholderia pseudomalleiclinical isolates are highly susceptiblein vitroto cefiderocol, a novel siderophore cephalosporin

Burnard

Robertson

Henderson

et al. 2020

Preprint

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“…In so doing, it overcomes multiple resistance mechanisms (e.g., porin channel deletion, efflux pump overexpression) while localizing the cephalosporin within the periplasm, adjacent to PBPs. Cefiderocol has in vitro activity against many Gram-negative bacteria, including CRE, P. aeruginosa, A. baumannii, and S. maltophilia In a study of 753 multidrug-resistant clinical isolates, including carbapenemase- and ESBL-producing bacteria, cefiderocol had superior in vitro activity to meropenem, ceftazidime, and ceftazidime-avibactam and equivalent activity to colistin and tigecycline [112]. A clinical trial for the treatment of nosocomial pneumonias comparing cefiderocol to meropenem, each in combination with linezolid, is underway (NCT03032380).…”

Section: Contemporary Treatment Strategies For Gram-negative Vapmentioning

confidence: 99%

Resistance Trends and Treatment Options in Gram-Negative Ventilator-Associated Pneumonia

Rhodes

Cruce

O’Donnell

et al. 2018

Curr Infect Dis Rep

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Rapid identification technologies and phenotypic methods, new therapeutic strategies, and novel treatment paradigms have evolved in an attempt to improve treatment outcomes for VAP; however, clinical data supporting alternative treatment strategies and adjunctive therapies remain sparse. Importantly, new classes of antimicrobials, novel virulence factor inhibitors, and beta-lactam/beta-lactamase inhibitor combinations are currently in development. Conscientious stewardship of new and emerging therapeutic agents will be needed to ensure they remain effective well into the future.

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“…As shown in Figure S4, CLI antagonized with DSX against PA14, thus the triple combination allowed more growth than CLI alone at its highest concentration. However, the triple combination reduces growth below the previously established MIC, 20% of control (21). D. TRO.…”

Section: Resultsmentioning

confidence: 80%

“…The catechol group of cefiderocol binds iron and the complex is taken up via PiuA, an outer-membrane receptor for iron transport (18, 19). The compound demonstrated potent activity against Escherichia coli and Klebsiella pneumoniae (19, 21). Thus, the Trojan horse approach enhances the delivery of antibiotics compared to diffusion alone.…”

Section: Introductionmentioning

confidence: 99%

Forging new antibiotic combinations under iron-limiting conditions

Chan

Guo

Burrows

2019

Preprint

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15Pseudomonas aeruginosa is a multidrug-resistant nosocomial pathogen. We showed previously that 16 thiostrepton (TS), a gram-positive thiopeptide antibiotic, was imported via pyoverdine receptors and 17 synergized with iron chelator deferasirox (DSX) to inhibit the growth of P. aeruginosa and Acinetobacter 18 baumannii clinical isolates. A small number of P. aeruginosa and A. baumannii isolates were resistant to the 19 combination, prompting us to search for other compounds that could synergize with TS against those 20 strains. From literature surveys we selected 14 compounds reported to have iron-chelating activity, plus 21 one iron analogue, and tested them for synergy with TS. Doxycycline (DOXY), ciclopirox olamine (CO), 22 during infection. To overcome iron limitation, P. aeruginosa produces the iron-scavenging siderophores 37 pyochelin and pyoverdine that bind iron with low and high affinity, respectively (3-5). Pyoverdine and its 38 outer membrane receptors, FpvA and FpvB, are highly expressed in low-iron conditions (3, 6, 7). Pyoverdine 39 has such a high binding affinity (10 32 M -1 ) for iron that it can strip it from transferrin, a mammalian protein 40 responsible for sequestering iron to impede bacterial growth (8-11). RNA-seq data showed that pyoverdine 41 biosynthetic enzymes and uptake are highly upregulated in vivo in response to the iron-deprived 42 environment (7). P. aeruginosa deficient in iron-uptake mechanisms are less able to cause infections 43 compared to their wild-type counterparts (12). 44 45 3 Natural products often exploit iron acquisition pathways to cross the Gram-negative outer membrane. 46 Pyocin S2, produced by P. aeruginosa to kill competing strains, and related toxins are taken up via FpvA (13, 47

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Activity of the novel siderophore cephalosporin cefiderocol against multidrug-resistant Gram-negative pathogens

Cited by 135 publications

References 18 publications

Burkholderia pseudomalleiclinical isolates are highly susceptiblein vitroto cefiderocol, a novel siderophore cephalosporin

Burkholderia pseudomalleiclinical isolates are highly susceptiblein vitroto cefiderocol, a novel siderophore cephalosporin

Resistance Trends and Treatment Options in Gram-Negative Ventilator-Associated Pneumonia

Forging new antibiotic combinations under iron-limiting conditions

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