Abstract: Heavy antibiotic usage is thought to contribute to the increased bacterial antibiotic resistance reported in intensive care units. Many units use extended-spectrum cephalosporins or fluoroquinolones as the empirical drug of choice; however, there are few reports documenting the effects of a switch from one class of antibiotics to another. A 2-year crossover study was undertaken on 2 large units, where the ecological effect of the implementation of a defined prescribing policy of 2 different antibiotic classes on the microflora of patients was examined. For the first year, cefotaxime or ceftazidime was the drug of choice for empirical treatment of patients. In the second year, this was changed to ciprofloxacin. Bacterial isolates from twice-weekly surveillance specimens and all clinical specimens were collected from 1026 patients. These were identified, and breakpoint susceptibility testing was conducted both during a 3-month baseline period and during the 2-year study period. Patient demographic data and antibiotic usage data were recorded throughout the study. There was a significant increase in the amount of ciprofloxacin used in the second year of the study and a decrease in the amount of cefotaxime or ceftazidime used. The decreased use of cephalosporins was linked with a decrease in ceftazidime-resistant Enterobacteriaceae organisms. The increased use of ciprofloxacin during the second year of the study did not seem to cause any significant rise in ciprofloxacin-resistant isolates. Although reducing the overall selective pressure by cutting antibiotic usage is important for controlling antibiotic resistance, our study illustrates the value of carefully considering which classes of antibiotic should be used for empirical therapy.