The hidden threat: Klebsiella pneumoniae may develop co-resistance to colistin and cefiderocol under pressure of colistin

Objectives: Carbapenem-resistant Klebsiella pneumoniae (CRKP) has become a global concern owing to its difficult treatment. This study aimed to determine the impact of colistin resistance on susceptibility to cefiderocol.

Methods: The colistin-susceptible clinical strain CRKP12-130 (colistin minimum inhibitory concentration [MIC] 0.5 mg/L) was cultured in medium containing 4× and 8× the MIC of colistin. Eight colistin-resistant derivatives were randomly selected for susceptibility testing of cefiderocol and zeta potential changes. To compare the impact of colistin resistance on bacterial uptake of iron, growth curve experiments were conducted in cation-adjusted Mueller-Hinton broth (CAMHB) and iron-depleted CAMHB (ID-CAMHB). Resistant strains and the original strain CRKP12-130 were subjected to next-generation sequencing.

Results: Colistin MICs ranged from 16 to 128 mg/L for the eight colistin-resistant derivatives. The key genetic variants identified in colistin-resistant strains involved insertions and deletions in mgrB, and missense mutations in pmrB and phoQ. The colistin-resistant derivatives also exhibited reduced susceptibility to cefiderocol, with MICs increasing from 1 mg/L to 2-8 mg/L. Additionally, colistin-resistant strains demonstrated higher zeta potentials, ranging from -45.2 mV to levels between -32.8 mV and -14.2 mV. Resistant strains showed a more significant decrease in growth rate when cultivated in ID-CAMHB medium.

Conclusion: This study investigated the phenomenon of co-resistance to colistin and cefiderocol in CRKP under pressure of colistin. The simultaneous decrease in susceptibility poses a potential threat to the efficacy of clinical treatment of CRKP infections.