Bacterial antibiotic resistance development and mutagenesis following exposure to subinhibitory concentrations of fluoroquinolones in vitro: a systematic review of the literature

BACKGROUND: Understanding social and scientific drivers of antibiotic resistance is critical to help preserve antibiotic efficacy. These drivers include exposure to subinhibitory antibiotic concentrations in the environment and clinic. OBJECTIVES: To summarize and quantify the relationship between subinhibitory fluoroquinolone exposure and antibiotic resistance and mutagenesis to better understand resistance patterns and mechanisms. METHODS: Following PRISMA guidelines, PubMed, Web of Science and Embase were searched for primary in vitro experimental studies on subinhibitory fluoroquinolone exposure and bacterial antibiotic resistance and mutagenesis, from earliest available dates through to 2018 without language limitation. A specifically developed non-weighted tool was used to assess risk of bias. RESULTS: Evidence from 62 eligible studies showed that subinhibitory fluoroquinolone exposure results in increased resistance to the selecting fluoroquinolone. Most increases in MIC were low (median minimum of 3.7-fold and median maximum of 32-fold) and may not be considered clinically relevant. Mechanistically, resistance is partly explained by target mutations but also changes in drug efflux. Collaterally, resistance to other fluoroquinolones and unrelated antibiotic classes also develops. The mean ± SD quality score for all studies was 2.6 ± 1.8 with a range of 0 (highest score) to 7 (lowest score). CONCLUSIONS: Low and moderate levels of resistance and efflux changes can create an opportunity for higher-level resistance or MDR. Future studies, to elucidate the genetic regulation of specific resistance mechanisms, and increased policies, including surveillance of low-level resistance changes or genomic surveillance of efflux pump genes and regulators, could serve as a predictor of MDR development.