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Development of cefiderocol resistance during treatment in Klebsiella pneumoniae
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International audience. BackgroundCefiderocol, a siderophore-conjugated cephalosporine, is a promising drug used to treat infection with carbapenem-resistant Gram-negative bacteria. Mutations in siderophore receptors are described to confer multiple levels of resistance to cefiderocol. Here we describe the emergence of resistance in clinical isolates of Klebsiella pneumoniae (KP) during treatment with cefiderocol.MethodsThree consecutive KP isolates were obtained from bronchoalveolar lavage of a patient with a ventilation-acquired pneumonia. Patient was hospitalized in the intensive care unit of the University Hospital of Poitiers, France. Antimicrobial susceptibility testing was assessed using Sensititre plates (EUMDROXF, ThermoFisher) and retrospectively with two cefiderocol broth microdilution assays (ComASP, Liofilchem; UMIC, Biocentric). Wholegenome sequencing was performed on the MinION Mk1b platform (Oxford Nanopore).ResultsAll isolates belonged to Sequence-Type 16 and were isogenic. First KP isolate (KP1) was resistant to almost all antibiotics tested, and harbored multiple resistance mechanisms to betalactams, including NDM-5 and CTX-M-15. In KP2 isolate, recovered after 18 days of cefiderocol treatment, mutation in fhuA was detected (Table). Third isolate (KP3) recovered after 30 days of treatment harbored additional mutations in cirA and fiu genes.Mutations in siderophore receptors were described in vitro to confer cefiderocol resistance, but reports of in vivo resistance are scarce. In the present case, the association of 3 mutations led to a high-level resistance. Antimicrobial susceptibility testing of cefiderocol is still challenging for microbiological laboratories, as of August 2022, EUCAST declared most available commercial tests had accuracy and reproducibility issues [1]. Mutations in fhuA gene were described as conferring slight elevation of cefiderocol MIC, that can be hard to detect using available assays. Thus, cefiderocol treatment was maintained. This probably led to the emergence of two additional mutations in cirA and fiu, conferring high-level resistanceto cefiderocol. MIC measurement performed with two other commercial assays (ComASP and UMIC) were able to detect the loss of susceptibility induced by the fhuA mutation.ConclusionsAntimicrobial susceptibility testing of cefiderocol remains an issue in clinical settings. Mutations in siderophore receptors like fhuA could confer a slight loss of cefiderocol susceptibility.
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