High in vitro activity of Fosfomycin in carbapenemase-producing Klebsiella pneumoniae and carbapenem-resistant Pseudomonas aeruginosa in clinical isolates in Colombia

Abstract

Objectives

We report the fosfomycin resistance rates in clinical isolates of carbapenemase-producing K. pneumoniae (CPKP) and carbapenem-resistant P. aeruginosa (CRPA) in Colombia, as well as the characterization of mechanisms of resistance to fosfomycin.

Methods

CPKP (n = 130) and CRPA (n = 170) isolates were collected from 12 Colombian hospitals between 2018 and 2022. Fosfomycin susceptibility testing was performed by agar dilution. Analysis of the MurA, GlpT, UhpT, UhpA, PtsI and CyaA were performed in all fosfomycin-resistant isolates using WGS.

Results

Minimal inhibitory concentrations below the ECOFFs were detected in 97,8 % isolates. Among the 5 fosfomycin-resistant CPKP, all isolates harbored a mutation in the MurA protein (Tyr287Asn) and a substitution (Gly171Arg) in the UhpT. 60 % fosfomycin-resistant CPKP had the Ile91Val mutation associated with the FosA^KPN, one isolate showed a substitution in the GlpT protein (Tyr141Cys), and one isolate displayed a premature stop codon of the GlpT (ES86). No mutations were found in GlpR, PtsI, or CyaA in CPKP resistant to fosfomycin. One fosfomycin-resistant CRPA isolate was identified, showing a deletion of 6 bp in glpT, as well as other mutation in the same gene, leading to the Gly422Ser substitution.

Conclusions

for CRPA and particularly, for CPKP resistant to fosfomycin, there is a diversity in their resistance mechanisms with mutations in the MurA as the prevalent mechanism in CPKP. Also, FosA^KPN and GlpT mutations were identified as the other mechanisms of fosfomycin resistance in these clinical isolates. Fosfomycin can be considered a therapeutic option in combination therapy to treat CPKP and CRPA in Colombia.