Unexpected natural cefiderocol resistance in Stenotrophomonas maltophilia associated to the genogroup 4 genetic background

Abstract

Objectives: Stenotrophomonas maltophilia (Sm) is responsible for infections in immunocompromised and hospitalized patients. Its genomic diversity has led to the description of a large complex including numerous genogroups. Regarding acquired resistances, cefiderocol (CeFiDeroCol, CFDC) is a promising therapeutic option. We aimed to evaluate the CFDC susceptibility of a large panel of Sm strains and explored the genetic support and background of resistance.

Methods: We prospectively collected 154 non-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 , core genome multi-locus sequence typing, and genogroup determination. CFDC susceptibility was tested using a two-step approach with a marketed product (screening step) and the broth microdilution method (confirmation step). Strains exhibiting an MIC >1 mg/L were considered as non-susceptible (ns). We used a national 2013 strain collection to confirm the resistance in a particular genogroup. The genetic support of CFDC non-susceptibility was studied according to a collection of previously selected CFDC mutants.

Results: Six of 154 Sm strains (4%) were non-susceptible to CFDC, including one environmental strain and five clinical strains. None of the patients was exposed to CFDC. The strains belonged to four different sequence type (ST) (ST87, n = 2; ST39, n = 2; ST18, n = 1; and unknown, n = 1) but to the same genogroup (genogroup 4). All seven 2013 genogroup 4 strains were also non-susceptible to CFDC. 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.

Discussion: The natural intrinsic non-susceptibility of the genogroup 4 could hamper the contribution of CFDC for the empiric treatment of Sm infections.

Keywords: Cefiderocol; Genetic background; Genogroup 4; Natural resistance; Stenotrophomonas maltophilia.