Fos resistance

[AntonS-bio]

I've noticed that program rarely reports resistance to fosfomycin (Fcyn) in Klebsiella pneumoniae. Given that vast majority of Kp samples carry FosA gene, is there another determinant apart from gene presence that is used for resistance identification? I couldn't find anything in code.

regard,
Anton

[katholt]

As you note, fosA is a core gene carried by ~all K. pneumoniae, however at wildtype expresssion levels, this chromosomal gene results in a fosfomycin MIC of only 16-32 mg/L, which is below the breakpoint for clinically relevant resistance. In contrast, the mobile form of fosA, which was captured from the K. pneumonie genome by IS26 and is under control of a strong IS26 promoter, is typically expressed at high enough levels to confer clinically relevant resistance.
The same is true of oqxAB and fluoroquinolone resistance (wildtype expression level of the chromosomal core gene confers ciprofloxacin MIC only 0.008-0.25 mg/L, below the breakpoints).
So, as all K. pneumoniae genomes carry these loci, simply detecting fosA or oqxAB in the assembly is not sufficient to assume resistance (deviation from wildtype), hence we do not report it.
In future releases we may address this by

• attempting to differentiate the mobile (ACQUIRED) from intrinsic forms of these loci, but this will require extensive testing and would always be dependent on the quality of the input genome assemblies
• add a column confirming the presence/absence of CORE genes of interest (fosA, oqxAB, mrk operon, etc).

[AntonS-bio]

This makes sense. As you suggest, an option or column that allows selective identification of intrinsic and acquired resistance would be very useful.