Pharmacokinetics and pharmacodynamics of aztreonam administered by continuous intravenous infusion

Abstract

The pharmacodynamic parameter that appears to correlate best with a successful therapeutic outcome with beta-lactam antibiotics is the length of time the serum antibiotic concentration remains above the minimum inhibitory concentration (MIC) for the infecting pathogen. By maximizing this parameter, continuous administration of beta-lactam and related antibiotics by intravenous infusion could represent the optimal mode of drug administration. The pharmacokinetic and pharmacodynamic properties of ceftazidime administered by continuous intravenous infusion have been evaluated previously. Aztreonam is a monobactam antibiotic with similar pharmacokinetic and microbiologic activity to that of ceftazidime. This study evaluated the pharmacokinetic and pharmacodynamic characteristics of aztreonam administered as a continuous intravenous infusion in healthy volunteers against multiple clinical isolates. Five men and 3 women received 6 g of aztreonam administered by continuous intravenous infusion over 24 hours. Blood samples were collected before the infusion and at 0.5, 1 through 8, 12, 18, and 24 hours after the start of the infusion. Pharmacokinetic parameters were determined by standard equations. In vitro susceptibility testing was performed using National Committee for Clinical Laboratory Standards guidelines for 4 clinical isolates of gram-negative bacteria (2 each of Escherichia coli and Pseudomonas aeruginosa). Serum inhibitory titers (SITs) were determined in duplicate for each clinical isolate at 0 and 24 hours. The subjects' mean (D) age was 29.3 .4 years; mean weight, 74.6 4.0 kg; and calculated mean creatinine clearance, 107 3 mL/min. For the pharmacokinetic parameters, mean (D) values were as follows: steady-state serum concentration, 40.9 .8 μg/L; halflife, 1.5 .4 hours; elimination rate constant, 0.50 ±0.13 hours −1; steady-state volume of distribution, 0.18 .04 L/kg; and total body clearance, 6.1 .2 L/h. The MICs were 0.0625 and 0.125 μg/mL against the 2 E coli isolates and 4 μg/mL against both P aeruginosa isolates. The median SITs against the E coli isolates were 1:256 and 1:512, and against the P aeruginosa isolates were 1:8 and 1:16. At steady state, 11 subjects had serum concentrations of aztreonam ≥4 times the MIC for each organism. These findings suggest that further clinical study of the administration of aztreonam by continuous intravenous infusion is warranted.