Multiple-dose pharmacokinetics of the monobactam azthreonam (SQ 26,776) in healthy subjects

Azthreonam, a monocyclic beta-lactam highly active against aerobic gram-negative bacteria in vitro, was administered to four groups of nine healthy male volunteers in the following four regimens: 500 mg intravenously (i.v.) over 2 min every 8 h, 1,000 mg i.v. over 2 min every 8 h, 500 mg intramuscularly (i.m.) every 8 h, and 1,000 mg i.m. every 8 h for 7 days. Serial samples of serum and urine were assayed by microbiological methods, and urine samples collected during the high-dose i.m. regimen were assayed by a high-pressure liquid chromatographic procedure. Mean peak serum levels were 39 and 99 micrograms/ml after the initial i.v. doses and 18 and 39 micrograms/ml after the initial i.m. doses. There was no evidence of drug accumulation. Mean serum trough levels were 1.0 and 2.5 micrograms/ml during the two i.v. regimens and 1.8 and 3.8 micrograms/ml during the two i.m. regimens. The mean difference among Cmax, area under the curve from 0 to 8 h, and urinary recovery at 0 to 8 h on days 1 and 8 was less than 13% for each regimen. From the i.v. study, the mean steady-state volume of distribution was 0.21 liter/kg, the terminal half-life was 1.6 h, serum clearance was 1.7 ml min-1 kg-1, urinary recovery was 60%, and serum protein binding was 56%. An average of about 6% of a 1,000-mg i.m. dose was excreted in the 8-h urine collection on day 8 as the open beta-lactam ring hydrolysis product of azthreonam. The concentrations of azthreonam in serum were within the range required to inhibit growth of susceptible organisms in vitro.