Clinical Pharmacokinetics of Aztreonam

Abstract

Aztreonam (azthreonam) is practically completely absorbed after intramuscular injection. After intravenous injection plasma concentrations follow a 2-compartment open model, with a t1/2 alpha of 0.20 hours. Volume of distribution at steady-state (Vdss) after intravenous or intramuscular injection is about 0.16 L/kg (0.42 L/kg for the free drug). After oral administration less than 1% of the drug is absorbed. Over a large dosage range plasma concentrations increase linearly with dose. No accumulation occurs after multiple dosing. Plasma binding in healthy subjects is about 56% and is not concentration dependent. Diffusion into tissues is generally slow, and the ratio between mean tissue and plasma concentration seems to depend mainly on the composition of the tissue. In inflamed meninges, penetration of aztreonam into CSF is more rapid than with uninflamed meninges. Diffusion through the placenta is poor, as is diffusion into breast milk. The main route of elimination of aztreonam is by the kidney, partly by active tubular excretion, but this can be inhibited by probenecid. Extrarenal clearance is probably due to excretion by the liver. Metabolism occurs to a very limited extent. Total plasma clearance in healthy adults is about 140 ml/min (8.4 L/h) or 2 ml/min/kg (0.12 L/h/kg), and terminal half-life is 1.7 hours. In children clearance is similar to that in adults when expressed as a function of bodyweight, but in neonates, especially in low birthweight infants, it is less [about 1 ml/min/kg (0.06 L/h/kg)]. In various disease states the Vdss of aztreonam is not appreciably different from that found in healthy individuals.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of Aztreonam in Healthy Subjects and Patients with Cystic Fibrosis and Evaluation of Dose-Exposure Relationships Using Monte Carlo Simulation

“…including the ␤-lactam antibiotics (12,37). In the present study the clearance in our control group was comparable to aztreonam clearance observed in healthy adults (1.31 versus 1.27 ml/min/kg) (24,39). Larger volumes of distribution have been primarily attributed to an increased amount of lean body mass (LBM) per kilogram of body weight and when corrected for LBM, or with allometric scaling when appropriate, most of these differences will disappear (3,32).…”

“…Volume estimates in our patients were in between those reported in children with CF (0.25 Ϯ 0.05 liter/kg) and those observed in healthy adults (0.16 Ϯ 0.2 liter/kg) (23,24). Increased total body clearance of ␤-lactams has been attributed to increased renal clearance, particularly tubular secretion.…”

“…20% higher in our patients. It has been reported that in healthy volunteers the renal clearance of unbound aztreonam exceeded the glomerular filtration rate and that probenecid diminished tubular secretion, indicating that active tubular secretion does occur (23,24). In the present study the renal clearance was about half the creatinine clearance, a surrogate marker for the glomerular filtration rate (Table 2).…”

“…The pharmacokinetics (PK) of aztreonam have been extensively studied in healthy subjects (38), as well as in a variety of small cohorts of patients with different underlying disease states (23,24,35), including patients with cystic fibrosis (CF) experiencing pulmonary exacerbations due to P. aeruginosa (6,7,33,34). Despite the fact that aztreonam has been on the market since the early 1980s, we are not aware of any PK data in the public domain related to adult patients with CF.…”

Bactericidal Kinetics of an in vitro Infection Model of Once-Daily Ceftriaxone plus Amikacin against Gram-Positive and Gram-Negative Bacteria

“…In this model once daily ceftriaxone and amikacin regimens resulted in >4 log kill within the first 5 h and inhibited the regrowth observed when the antibiotics were used alone, as described by other authors [19]. Re growth after antibiotic exposure depends on several factors.…”