DESCRIPTION (provided by applicant): Resistance to the fluoroquinolone (FQ) antibiotics is particularly concerning for Escherichia coli, the most common cause of outpatient urinary tract infections (UTIs). UTIs are the most common outpatient bacterial infection with significant clinical and economic implications. Antibiotic susceptibility is typically reported as "susceptible, "intermediate", or "resistant". However, it has been suggested that FQ-susceptible E. coli (FQSEC) can be further divided into two groups based on the minimum inhibitory concentration (MIC) value: 1) "Low-MIC FQSEC" (or LM-FQSEC) (levofloxacin MIC d0.12 mcg/ml); and 2) "High-MIC FQSEC" (or HM- FQSEC) (levofloxacin MIC >0.12 but <4 mcg/ml). These groups have also been referred to as "fully susceptible" and "reduced susceptible" strains, respectively. There is a clear rationale for distinguishing HM- FQSEC and LM-FQSEC. Specifically, while still within the susceptible range, HM-FQSEC isolates typically harbor at least one FQ resistance mechanism (e.g., gyrA mutation). Treatment of an HM-FQSEC with a FQ agent exerts selective pressure on the organism to acquire additional FQ resistance mechanisms. This not only increases the likelihood of treatment failure, but also drives further increases in the reservoir o FQ- resistant organisms. Risk factors for HM-FQSEC UTI are unknown. Furthermore, the impact of HM-FQSEC on FQ treatment failure has not been studied. Finally, the relationship between HM-FQSEC and underlying FQ resistance mechanisms and strain type are unknown. This study has two specific aims: Aim 1: To identify risk factors for HM-FQSEC among outpatient UTIs; Aim 2: To determine the association between HM-FQSEC and treatment failure among outpatients with UTIs who receive FQ therapy. The primary hypotheses for these aims are: 1) prior FQ use is associated with HM-FQSEC; and 3) HM-FQSEC is associated with FQ treatment failure. This study also has two secondary aims: Secondary Aim 1: To determine the impact of organism characteristics (i.e., FQ resistance mechanisms, strain type) on risk factors for HM-FQSEC. Secondary Aim 2: To determine the impact of organism characteristics (i.e., FQ resistance mechanisms, strain type) on the association between HM-FQSEC and FQ treatment failure. This study will provide important insights with regard to which modifiable variables might be targeted to curtail further emergence of FQ resistance. This work will also be invaluable in informing antibiotic prescribing for E. coli UTIs. Finally, this study will provide critical detail of the relationship between HM-FQSEC and the underlying FQ resistance mechanism(s) and strain type 1.

PUBLIC HEALTH RELEVANCE: Resistance to the fluoroquinolone (FQ) antibiotic class has increased greatly in recent years. This is particularly concerning for Escherichia coli, the most common cause of outpatient urinary tract infections (UTIs). Even among FQ-susceptible E. coli (FQSEC), there are some organisms that harbor one or more FQ resistance mechanisms. This study will identify risk factors for such organisms and determine the impact of such organisms on FQ treatment failure. Results from this study will be vital for designing future interventions t limit further increases in FQ resistance and optimize antibiotic treatment for outpatient UTIs. 1