Natural Cefiderocol Resistance in Stenotrophomonas maltophilia Genogroup 4

Background : Stenotrophomonas maltophilia (Sm) is responsible for infections among immunocompromised and hospitalized patients. Its genomic diversity led to the description of a large complex including numerous genogroups. Regarding the emergence of acquired resistance, cefiderocol (FDC) has emerged as a promising therapeutic option. We tested its susceptibility against a large panel of strains and explored the genetic support and background of resistance. Methods : We prospectively collected 154 duplicated clinical and environmental strains from five university hospitals between January 2023 and April 2024. All the strains were whole genome sequenced and their genetic background studied using Multi-Locus Sequence Typing (MLST), core genome MLST and genogroup determination. FDC susceptibility was tested using the broth microdilution method. Strains exhibited a MIC > 2 mg/L were considered as FDC-ns. A national 2013 collection of strains was used to confirm the findings. The genetic support of FDC non-susceptibility was studied using (i) a collection of previously selected FDC mutants and (ii) a GWAS approach. Results : Six out of 154 Sm strains (4%) were FDC-ns, including one environmental and five clinical strains. None of the patients was exposed to FDC. The MIC ranged from 2 to 8 mg/L. The strains belonged to four different ST (ST87, n=2; ST39, n= 2; ST18, n=1, unknown, n=1) but to the same genogroup (genogroup 4). All the seven 2013 genogroup 4 strains were also FDC-ns. All the 13 strains were highly resistant to ceftazidime-avibactam. None of the previously published mutations/deletions were identified but common non-synonymous mutations were found in tonB and tolQ; a common polymorphism was identified in the promoter region of smet. The GWAS approach identified a set of genes whose function mostly remains to be determined. Conclusions : The natural intrinsic non-susceptibility of the genogroup 4 could hamper the contribution of FDC for the empiric treatment of Sm infections.