The multiple-dose pharmacokinetics and safety of ciprofloxacin, a new quinoline carboxylic acid derivative, were evaluated in normal volunteers. The drug was administered orally every 12 h during successive 7-day periods at doses of 250, 500, and 750 mg. Samples of serum, urine, and saliva obtained after the first dose on days 1, 4, and 7 of each dosing period were assayed by microbiological methods. Peak concentrations of ciprofloxacin in serum were achieved generally from 1 to 1.5 h after administration. Mean peak serum levels were 1.35 to 1.42 ,ug/ml after the 250-mg dose, 2.60 to 2.89 ,ug/ml after the 500-mg dose, and 3.41 to 4.21 ,ug/ml after the 750-mg dose. Terminal serum half-lives ranged from 3.8 to 4.3, 4.5 to 4.9, and 3.9 to 6.6 h after the 250-, 500-, and 750-mg doses, respectively. Mean concentrations of ciprofloxacin in urine samples collected 0 to 2 h after dosing were 205 to 261, 255 to 518, and 243 to 846 ,ug/ml after the 250-, 500-, and 750-mg doses, respectively. Between 30 and 45% of the dose was recovered in urine 0 to 12 h after drug administration. Mean concentrations of ciprofloxacin in saliva at 2 h after dosing were 0.43, 1.23, and 1.45 ,Ig/ml after the 250-, 500-, and 750-mg doses, respectively. These levels were 30 to 45% of the peak levels in serum and between 40 and 65% of the levels in serum measured 2 h after dosing. Ciprofloxacin was well tolerated.

We are reporting on a nosocomial outbreak of 213 cases of vancomycin-resistant enterococcus infection involving 2,812 enterococcal isolates from patients over a period of 36 months. In 1990, the Enterococcus faecium vancomycin susceptibility rate was found to be 85.7% (36 of 42 cases), and an incidence of 10.9%o (42 of 383) was noted. The 1991 data showed E.faecium with a vancomycin susceptibility rate of 61.8% (110 of 178) and an incidence of 26.0%,o (178 of 684). Subsequently, in 1992, the incidence ofE.faecium increased to 34.0%yV (599 of 1,745), with a decreased vancomycin susceptibility rate of 25.8% (155 of 599). The E. faecalis vancomycin susceptibility rate remained near 97% (1,768 of 1,823) over the 36-month period. Of 115

The effect of dose or dose interval on the pharmacodynamics of simulated high-dose intravenous ciprofloxacin therapy on infection due to Pseudomonas aeruginosa and Staphylococcus aureus was studied in an in vitro hollow-fiber model of infection. Simulated doses of 1,200 mg of ciprofloxacin per day as either 400 mg every 8 h or 600 mg every 12 h against P. aeruginosa resulted in selection of ciprofloxacin-resistant bacteria. The results with one test strain that was isolated from a patient prior to administration of intravenous ciprofloxacin demonstrated selection of a gyrA mutant in the model, as had occurred in vivo. A single 1,200-mg dose every 24 h did not select for bacterial resistance; however, breakthrough regrowth of ciprofloxacin-susceptible bacteria occurred. Dosages of 400 or 600 mg of ciprofloxacin every 12 h effectively reduced bacterial counts of one strain each of methicillin-susceptible or -resistant S. aureus, with no bacterial resistance detected at the end of experiment; in contrast, 200 mg every 12 h resulted in bacterial regrowth due to the selection of drug-resistant bacteria. These data show the need for high-dose intravenous ciprofloxacin, particularly with regimens producing high peak levels, for treatment of infections where selection for bacterial resistance is a clinical problem.