Objective: We observed an overall increase in the use of third- and fourth-generation cephalosporins after fluoroquinolone preauthorization was implemented. We examined the change in specific third- and fourth-generation cephalosporin use, and we sought to determine whether there was a consequent change in non-susceptibility of select Gram-negative bacterial isolates to these antibiotics. Design: Retrospective quasi-experimental study. Setting: Academic hospital. Intervention: Fluoroquinolone preauthorization was implemented in the hospital in October 2005. We used interrupted time series (ITS) Poisson regression models to examine trends in monthly rates of ceftriaxone, ceftazidime, and cefepime use and trends in yearly rates of nonsusceptible isolates (NSIs) of select Gram-negative bacteria before (1998-2004) and after (2006-2016) fluoroquinolone preauthorization was implemented. Results: Rates of use of ceftriaxone and cefepime increased after fluoroquinolone preauthorization was implemented (ceftriaxone RR, 1.002; 95% CI, 1.002-1.003; P <.0001; cefepime RR, 1.003; 95% CI, 1.001-1.004; P =.0006), but ceftazidime use continued to decline (RR, 0.991, 95% CI, 0.990-0.992; P <.0001). Rates of ceftazidime and cefepime NSIs of Pseudomonas aeruginosa (ceftazidime RR, 0.937; 95% CI, 0.910-0.965, P <.0001; cefepime RR, 0.937; 95% CI, 0.912-0.963; P <.0001) declined after fluoroquinolone preauthorization was implemented. Rates of ceftazidime and cefepime NSIs of Enterobacter cloacae (ceftazidime RR, 1.116; 95% CI, 1.078-1.154; P <.0001; cefepime RR, 1.198; 95% CI, 1.112-1.291; P <.0001) and cefepime NSI of Acinetobacter baumannii (RR, 1.169; 95% CI, 1.081-1.263; P <.0001) were increasing before fluoroquinolone preauthorization was implemented but became stable thereafter: E. cloacae (ceftazidime RR, 0.987; 95% CI, 0.948-1.028; P =.531; cefepime RR, 0.990; 95% CI, 0.962-1.018; P =.461) and A. baumannii (cefepime RR, 0.972; 95% CI, 0.939-1.006; P =.100). Conclusions: Fluoroquinolone preauthorization may increase use of unrestricted third- and fourth-generation cephalosporins; however, we did not observe increased antimicrobial resistance to these agents, especially among clinically important Gram-negative bacteria known for hospital-acquired infections.