In Vitro Activity of Cefiderocol, a Siderophore Cephalosporin, Against Gram-Negative Bacilli Isolated by Clinical Laboratories in North America and Europe in 2015-2016: SIDERO-WT-2015

Karlowsky, James A.; Hackel, Meredith; Tsuji, Masakatsu; Yamano, Yoshinori; Echols, Roger; Sahm, Daniel F.

doi:10.1016/j.ijantimicag.2018.11.007

Cited by 129 publications

(146 citation statements)

References 18 publications

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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: 75%

“…Subsequent isolate C5 exhibited a multidrug resistant profile with resistance to meropenem, amoxicillin-clavulanic acid, trimethoprim-sulfamethoxazole, doxycycline, non-susceptibility to ceftazidime and a cefiderocol MIC of 8 mg/L. Previous studies have highlighted that cefiderocol activity is not generally impacted by resistance to other antimicrobials 5–7,13,32 . In this study, amoxicillin-clavulanic acid resistance does not appear to impact cefiderocol or ceftazidime MICs.…”

Section: Discussionmentioning

confidence: 98%

“…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 . The increase in MIC may be influenced by the increase in sample size, however larger samples sizes have not substantially increased the MIC 90 of cefiderocol in other pathogens such as P. aeruginosa, A. baumannii, K. pneumoniae and E. coli 13,31,32 . Moreover, sister species B. mallei has an MIC 90 of 4 mg/L from 30 isolates, significantly higher than that observed in B. pseudomallei 14 , whereas isolates from the closely related B. cepacia complex also exhibit a consistently low MIC 90 of 0.016 and 0.12 mg/L, despite small sample sizes in ID-CAMHB media 5,13 .…”

Section: Discussionmentioning

confidence: 99%

“…Cefiderocol recently received FDA approval for the treatment of complicated urinary tract infections 9 , on the basis of non-inferiority against imipenem/cilastatin 10 . A trial versus meropenem for nosocomial pneumonia has also been completed 5,11 with efficacy demonstrated against Gram-negative pathogens such as Enterobacterales, Pseudomonas aeruginosa and Acinetobacter baumannii 12,13 . Provisional CLSI in vitro breakpoints have been set at ≤4 mg/L (S) and ≥16 mg/L (R) respectively for these pathogens 12 .…”

Section: Introductionmentioning

confidence: 99%

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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: 75%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Burnard

Robertson

Henderson

et al. 2020

Preprint

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“…Compared with ceftazidime-avibactam, cefiderocol has similar in vitro microbiological activity against Enterobacterales and P. aeruginosa, but it is more active against Acinetobacter, Stenotrophomonas and Burkholderia species. The resist ance prevalence in CRE and CRPA is a little lower than with ceftazidime-avibactam 64 . The main weakness of cefiderocol is its limited activity against NDM producing E. coli as well as OXA23 producing and OXA24 producing Acinetobacter spp 65 .…”

Section: New Stand-alone β-Lactam Antibioticsmentioning

confidence: 82%

Critical analysis of antibacterial agents in clinical development

Theuretzbacher¹,

et al. 2020

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| The antibacterial agents currently in clinical development are predominantly derivatives of well-established antibiotic classes and were selected to address the class-specific resistance mechanisms and determinants that were known at the time of their discovery. Many of these agents aim to target the antibiotic-resistant priority pathogens listed by the WHO, including Gram-negative bacteria in the critical priority category, such as carbapenem-resistant Acinetobacter, Pseudomonas and Enterobacterales. Although some current compounds in the pipeline have exhibited increased susceptibility rates in surveillance studies that depend on geography, pre-existing cross-resistance both within and across antibacterial classes limits the activity of many of the new agents against the most extensively drug-resistant (XDR) and pan-drug-resistant (PDR) Gram-negative pathogens. In particular, cross-resistance to unrelated classes may occur by co-selection of resistant strains, thus leading to the rapid emergence and subsequent spread of resistance. There is a continued need for innovation and new-class antibacterial agents in order to provide effective therapeutic options against infections specifically caused by XDR and PDR Gram-negative bacteria. ✉

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Medicinal Chemistry of β‐Lactam Antibiotics

Testero

Llarrull

Fisher

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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The β‐lactam class of antibacterials is a cornerstone of human health. For nearly eight decades, their unparalleled clinical efficacy and clinical safety have made the β‐lactam class preeminent in the treatment of bacterial infection. The relatively brief period in human history during which the β‐lactams have exerted this benefit is a period characterized by continuous medicinal chemistry innovation, seen visibly in the progression from the penicillins to the complex ensemble of β‐lactams (now including also cephalosporins, monobactams, and carbapenems) used in the clinic. The key force behind this innovation is the progressive evolution by bacteria of resistance mechanisms. Today, highly resistant bacteria challenge the way medicinal chemists contemplate the creative alteration of β‐lactam structures, the way the pharmaceutical industry develops β‐lactams (and other antibacterial) structures, and the way the medical community uses antibacterials. This article gives a concise summary of the history of the β‐lactams. Its emphasis is recent structural innovation with respect to the β‐lactams, and with respect to structurally related classes that act to preserve the clinical activity of the β‐lactams through inhibition of bacterial β‐lactam‐hydrolyzing, and thus β‐lactam‐deactivating, enzymes. We integrate these chemistry advances with new biological discoveries with respect to the bactericidal mechanism of the β‐lactams and with respect to bacterial resistance mechanisms. The combination of these perspectives is a foundational perspective to guide the medicinal chemistry future of the β‐lactams.

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In Vitro Activity of Cefiderocol, a Siderophore Cephalosporin, Against Gram-Negative Bacilli Isolated by Clinical Laboratories in North America and Europe in 2015-2016: SIDERO-WT-2015

Cited by 129 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

Critical analysis of antibacterial agents in clinical development

Medicinal Chemistry of β‐Lactam Antibiotics

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