To compare rates of treatment failure for patients with bloodstream infections (BSIs) due to Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis who received oral step-down antibiotic therapy with either a fluoroquinolone (FQ) or trimethoprim/sulfamethoxazole (SXT) to rates for those who received an oral β-lactam (BL). This retrospective, multicenter, cohort study included 397 unique adult hospitalized patients with a BSI due to E. coli, K. pneumoniae, or P. mirabilis at 6 hospitals in central Texas between July 11, 2016, and July 11, 2018. The primary outcome was a composite of treatment failure comprising 30-day readmission due to recurrence, 30-day all-cause mortality, and change in oral antibiotic. Secondary outcomes included 90-day development of Clostridioides difficile infection, 90-day colonization with a multidrug-resistant organism, 90-day all-cause readmission, hospital length of stay, and the individual components of the primary outcome. Of the 397 patients included, 200 received oral step-down therapy with a BL while 197 received an FQ or SXT. Most patients had an infection due to E. coli (82.8%) and a urinary source of infection (85%). Median total duration of therapy was 14 days in both groups. No difference in treatment failure was identified between the groups treated with a BL and FQ/SXT (7% vs 5.8%, P = 0.561). Median hospital length of stay was the only secondary endpoint in which there was an observed difference (6 vs 5 days, P = 0.04). We observed no difference in treatment failure rates for patients receiving an oral BL compared to an oral FQ or SXT for step-down therapy of BSIs due to E. coli, K. pneumoniae, and P. mirabilis.