Establishing Genotypic Cutoff Values To Measure Antimicrobial Resistance in Salmonella

Abstract

Whole-genome sequencing (WGS) has transformed our understanding of antimicrobial resistance, helping us to better identify and track the genetic mechanisms underlying phenotypic resistance. Previous studies have demonstrated high correlations between phenotypic resistance and the presence of known resistance determinants. However, there has never been a large-scale assessment of how well resistance genotypes correspond to specific MICs. We performed antimicrobial susceptibility testing and WGS of 1,738 nontyphoidal Salmonella strains to correlate over 20,000 MICs with resistance determinants. Using these data, we established what we term genotypic cutoff values (GCVs) for 13 antimicrobials against Salmonella. For the drugs we tested, we define a GCV as the highest MIC of isolates in a population devoid of known acquired resistance mechanisms. This definition of GCV is distinct from epidemiological cutoff values (ECVs or ECOFFs), which currently differentiate wild-type from non-wild-type strains based on MIC distributions alone without regard to genetic information. Due to the large number of isolates involved, we observed distinct MIC distributions for isolates with different resistance gene alleles, including for ciprofloxacin and tetracycline, suggesting the potential to predict MICs based on WGS data alone.

Using the NCBI AMRFinder Tool to Determine Antimicrobial Resistance Genotype-Phenotype Correlations Within a Collection of NARMS Isolates

“…As expected, we observed that 718 out of 725 S. enterica isolates (99.0%) with one or more bla CMY - family genes were resistant to amoxicillin-clavulanic acid. As observed previously (51), other beta-lactamases conferred decreased or intermediate susceptibility to amoxicillin-clavulanic acid (Fig. 3).…”

“…S. enterica displayed high consistency for both ciprofloxacin and nalidixic acid (Table 2). When decreased susceptibility (R or I) is used as the breakpoint for ciprofloxacin (51), S. enterica isolates had high positive predictive values (PPV = 0.891) and high negative predictive values (NPV = 0.997). For nalidixic acid, the positive predictive value was quite low (PPV = 0.3).…”

Genome annotation and antimicrobial properties of Bacillus toyonensis VU‐DES13, isolated from the Folsomia candida gut

“…Interestingly, from the analysis by the Resfam databases it became apparent that Bacillus VU-DES13 contains 13 additional b-lactams when compared to the BCT-7112 T genome, which may explain its high resistance to the b-lactam penicillin. This would support the genotypic cutoff concept, linking the distribution of resistance alleles to MIC (Tyson et al, 2017). Antibiotic producers can evolve mechanisms to protect themselves from the compounds they are producing (Hopwood, 2007).…”

Accelerating surveillance and research of antimicrobial resistance – an online repository for sharing of antimicrobial susceptibility data associated with whole genome sequences

“…A total of 470 E. coli antibiograms were submitted directly by COMPARE partners while 107 were imported from the US CDC database (n = 31) or previous publications (n = 76) 10,11 .…”

“…Contributing institutions for AST data: Amsterdam UMC 1 , APHA 11 , DTU 2 , FM 7 , OUCRU 13 , SSH 12 , UNIBO 10 .…”