Quantifying the contribution of four resistance mechanisms to ciprofloxacin MIC in Escherichia coli: a systematic review

Background: Reviews assessing the genetic basis of ciprofloxacin resistance in Escherichia coli have mostly been qualitative. However, to predict resistance phenotypes based on genotypic characteristics, it is essential to quan- tify the contribution of genotypic determinants to resistance. Objectives: We performed a systematic review to assess the relative contribution of known genomic resistance determinants to the MIC of ciprofloxacin in E. coli. Methods: PubMed and Web of Science were searched for English language studies that assessed ciprofloxacin MIC and presence or introduction of genetic determinants of ciprofloxacin resistance in E. coli. We included ex- perimental and observational studies without time restrictions. Medians and ranges of MIC fold changes were calculated for individual resistance determinants and combinations thereof. Results: We included 66 studies, describing 604 E. coli isolates that carried at least one genetic ciprofloxacin re- sistance determinant. Mutations in gyrA and parC, genes encoding targets of ciprofloxacin, contribute to the larg- est fold changes in ciprofloxacin resistance in E. coli compared with the WT. Efflux and physical blocking or enzymatic modifications confer smaller increases in ciprofloxacin MIC than mutations in gyrA and parC. However, the presence of these other resistance mechanisms in addition to target alteration mutations further increases ciprofloxacin MIC, thus resulting in ciprofloxacin MIC increases ranging from 250- to 4000-fold. Conclusions: This quantitative review of genomic determinants of ciprofloxacin resistance in E. coli demon- strates the complexity of resistance phenotype prediction from genomic data and serves as a reference point for studies aiming to predict ciprofloxacin MIC from E. coli genomes.