# P-1197. NDM-5 and Siderophore Receptor Mutations Drive High Level Cefiderocol Resistance in Klebsiella pneumoniae: A Case Series

## TL;DR

This study reports on 12 patients with cefiderocol-resistant Klebsiella pneumoniae infections, showing that NDM-5 and siderophore receptor mutations contribute to high-level antibiotic resistance.

## Contribution

The study identifies NDM-5 and specific siderophore receptor mutations as key drivers of cefiderocol resistance in Klebsiella pneumoniae.

## Key findings

- All 9 sequenced isolates carried the NDM-5 gene, linked to high-level cefiderocol resistance.
- Siderophore receptor mutations were associated with resistance in NDM-5 producing K. pneumoniae.
- Ceftazidime-avibactam plus aztreonam was effective in most cases, though some patients experienced recurrence.

## Abstract

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.Table 1:Baseline CharacteristicsCNS = central nervous system, LTCF = long-term care facilities, MIC = minimum inhibitory concentration, NDM = New Delhi metallo-beta-lactamase, OSH = outside hospital, SSTI = skin and soft tissue infection, UTI = urinary tract infectionTable 2:Outcomes1Patient was switched from tigecycline to ceftazidime/avibactam + aztreonam due to breakthrough bacteremia with the same NDM K. pneumoniae2Patient was switched from ceftazidime/avibactam + aztreonam to meropenem/vaborbactam + aztreonam due to polymicrobial infection with an E. coli that was resistant to ceftazidime/avibactam but susceptible to meropenem/vaborbactam3Recurrence was treated with ceftazidime/avibactam + aztreonam for 7 days

Baseline Characteristics

CNS = central nervous system, LTCF = long-term care facilities, MIC = minimum inhibitory concentration, NDM = New Delhi metallo-beta-lactamase, OSH = outside hospital, SSTI = skin and soft tissue infection, UTI = urinary tract infection

Outcomes

1Patient was switched from tigecycline to ceftazidime/avibactam + aztreonam due to breakthrough bacteremia with the same NDM K. pneumoniae

2Patient was switched from ceftazidime/avibactam + aztreonam to meropenem/vaborbactam + aztreonam due to polymicrobial infection with an E. coli that was resistant to ceftazidime/avibactam but susceptible to meropenem/vaborbactam

3Recurrence was treated with ceftazidime/avibactam + aztreonam for 7 days

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 was performed to analyze resistance mechanisms, as well as mutations in siderophore transporters and porins.Whole Genome Sequencing Results

Whole Genome Sequencing 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. Treatment with ceftazidime-avibactam plus aztreonam was successful in most instances, although microbiologic recurrence occurred in certain cases.

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.

Emir Kobic, BCIDP, Shionogi: Honoraria