Two regimens for infusing vancomycin over 1 h (500 mg every 6 h for five doses or 100 mg every 12 h for three doses) were used in 11 volunteers. Subjects received both regimens one week apart; the regimen used first for each subject was randomized. Nine receiving the 1000-mg dose experienced the "red-man (neck)" syndrome; none had the reaction while receiving the 500-mg dose (P = .002). Plasma histamine concentration, measured every 10 min during the first infusion of each regimen, increased in most subjects given 1000-mg doses; there was only a slight change in histamine levels after 500-mg doses. There was a significant relation between histamine release and reaction severity; frequency and severity of the reaction declined with subsequent doses. We conclude that the red-man syndrome occurs frequently in normal adults who receive 1000 mg of vancomycin over 1 h, that vancomycin causes an infusion rate-dependent increase in plasma histamine concentration, and that the increase in plasma histamine concentration is correlated with the severity of the reaction.

A pharmacokinetic comparison of the two recommended dosages of vancomycin given as multiple doses has not been previously performed. Eleven adult subjects with normal renal function randomly received 500 mg every 6 h (five doses) and, later, 1,000 mg every 12 h (three doses). Each dose was infused over 1 h, and regimens were separated by 1 week. Compared with the two-compartment fit, a three-compartment fit significantly reduced the residual weighted sums of squares. Accumulation occurred for both regimens after repeated dosing and was independent of dose. At steady state, concentrations in serum at 1 h showed little variation for the 1,000- or the 500-mg dose regimen (33.7 +/- 3.8 versus 22.6 +/- 3.2 micrograms/ml); trough concentrations were 7.9 +/- 1.7 versus 11.2 +/- 2.2 micrograms/ml, respectively. With the 1,000-mg dose, the terminal half-life was 7.7 +/- 1.8 h, steady-state area under the curve for the dose interval was 227 +/- 28.3 micrograms X h/ml, and total body clearance was 86.1 +/- 8.9 ml/min per 1.73 m2. The red-man syndrome occurred in 9 of 11 volunteers who received 1,000-mg doses and in none of those who received 500-mg doses. We concluded that vancomycin disposition in healthy adults with normal renal function is best described by a three-compartment model, there is relatively little variation in vancomycin disposition in normal volunteers, significant accumulation occurs with multiple dosing, it is inappropriate to use the same therapeutic window for both regimens, and the pharmacokinetics of vancomycin justify a 12-h dose interval; however, a 1-g dose is associated with a significantly greater incidence of the red-man syndrome.