NDM-5 and siderophore receptor mutations drive high-level cefiderocol resistance in Klebsiella pneumoniae: a case series.

Background: Infections with Carbapenem-resistant Enterobacterales (CREs) are a serious public health threat. The emergence of distinct New Delhi metallo-beta-lactamase (NDM)-producing K. pneumoniae strains resistant to cefiderocol is a significant concern given the limited armamentarium for these carbapenemases.

Methods: A case series of 12 patients was described from a single institution that had cefiderocol-resistant, NDM-producing K. pneumoniae infections between January 2023 and July 2024. Whole genome sequencing with core SNP analysis was performed to identify resistance mechanisms and clonal relatedness for 9 isolates.

Results: Patients presented with various infections, including skin and soft tissue infections, pneumonia, and bacteremia. Of concern, cefiderocol resistance was seen among patients with and without prior cefiderocol exposure. Genomic analysis for 9 patients revealed NDM-5 in every isolate, along with additional mutations associated with resistance. A cluster of ST147 identified multiple distinct CirA disruptions, suggestive of convergent evolution with or without cefiderocol exposure. Treatment with either ceftazidime-avibactam plus aztreonam or tigecycline was successful in most instances, although microbiologic recurrence occurred in certain cases.

Conclusion: High level cefiderocol resistance among NDM-5 producing K. pneumoniae with siderophore mutations add more challenges to treating CRE infections. Stricter infection control measures along with enhanced surveillance are needed, especially in regions where NDM is endemic to limit additional spread of these variants.