Background: Severe acute uncomplicated pyelonephritis is an infection of the kidneys that usually have an ascending route and occur in presumably healthy urinary tract. The most common pathogen involved is E. coli. The Infectious Diseases Society of America (IDSA) has issued an updated guideline in 2010 suggesting IV quinolones to be considered in the initial empiric antimicrobial therapy giving known resistance of less than 10%. However, E. coli resistance to quinolones has been increasing, the recent data of E. coli, causing pyelonephritis, resistance is not known in the Midwest. Local hospital antibiogram for two years showed up to 22% resistance to ciprofloxacin among E. coli isolates. Methods: We conduct a retrospective non-concurrent cohort study in one teaching hospital in the Midwest, females who were admitted with severe acute uncomplicated pyelonephritis in a three years period were included. Patients with urinary tract obstruction, pregnancy, immuno-suppression, males, and indwelling Foley’s catheters were excluded. Data collected include causative pathogens and resistance to antibiotics were collected. Percentages, frequencies, and measures of central tendency and dispersion were calculated to describe the study sample Results: 73 patients were included in the final analysis. E. coli was the most common isolated pathogen (81%), followed by other enteric gram negative. E. coli resistance to ciprofloxacin was 13.5%, 37% to trimethoprim-sulfamethoxazole, and 5% to ceftriaxone. Conclusion: Ciprofloxacin should be avoided initially in treating severe acute uncomplicated pyelonephritis until culture results and sensitivity is available.