Ciprofloxacin is important for treatment of severe or invasive Salmonella infections in humans. As laboratories transition from phenotypic to genomics-based methods for determining ciprofloxacin non-susceptibility, it is important to define the correlation between genetic determinants of resistance and phenotypic outcomes. Here, we examined ciprofloxacin resistance mechanisms in Salmonella and tested the hypothesis that isolates containing only one mechanism had intermediate resistance while isolates containing two or more mechanisms had full resistance according to breakpoints from the Clinical Laboratory Standards Institute. Among 13,750 human and food/animal Salmonella enterica isolates, 2325 were predicted to be non-susceptible to ciprofloxacin using whole genome sequencing and Staramr. The most common mechanisms of resistance were mutations in gyrA (especially S83F and D87N/D87Y) and the qnrB19 allele. Only 28% of ciprofloxacin resistant isolates had two or more resistance mechanisms
the remainder contained only one mechanism. Of isolates with two or more mechanisms, only 63% were resistant. Thus, the number of genetic determinants of ciprofloxacin resistance in an isolate could not reliably differentiate the ciprofloxacin intermediate or resistant categories when using North American breakpoints. Predicting ciprofloxacin intermediate/resistant as a single non-susceptible category would facilitate global standardization of data to inform public health surveillance, treatment guidelines and stewardship.