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Antimicrobial Agents and Chemotherapy, September 2007, p. 3049-3055, Vol. 51, No. 9
0066-4804/07/$08.00+0     doi:10.1128/AAC.01522-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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

Alexander A. Vinks,1* Ronald N. van Rossem,2 Ron A. A. Mathôt,3 Harry G. M. Heijerman,4 and Johan W. Mouton5

Pediatric Pharmacology Research Unit, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Department of Pediatrics, Cincinnati, Ohio,1 Reinier de Graaf Hospitals Delft/Voorburg, Delft, The Netherlands,2 Department of Hospital Pharmacy, Erasmus Medical Center, Rotterdam, The Netherlands,3 Adult CF Center, Haga Hospital, The Hague, The Netherlands,4 Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands5

Received 4 December 2006/ Returned for modification 8 March 2007/ Accepted 9 June 2007

Aztreonam (AZM) is a monobactam antibiotic with a high level of activity against gram-negative micro-organisms, including Pseudomonas aeruginosa. We evaluated AZM pharmacokinetics and pharmacokinetic-pharmacodynamic relationships in patients with cystic fibrosis (CF) and healthy subjects. Pharmacokinetic data in eight CF patients and healthy subjects that were matched for age, gender, weight, and height were obtained and analyzed by using the nonparametric adaptive grid algorithm. Probabilities of target attainment using percentages of time of unbound concentration above the MIC (fT>MIC) were obtained by using a Monte Carlo simulation. AZM total body clearance was significantly higher in CF patients (100.1 ± 17.1 versus 76.2 ± 7.4 ml/min in healthy subjects; P < 0.01). The pharmacokinetic parameter estimates for terminal half-life (1.54 ± 0.17 h [mean ± the standard deviation]) and volume of distribution (0.20 ± 0.02 liters/kg in patients with CF patients were not different from those in healthy subjects. Monte Carlo simulations with a target of a fT>MIC of 50 to 60% at a dose of 1,000 mg every 8 h indicated a clinical breakpoint of 4 mg/liter and 1 to 2 mg/liter for healthy subjects and CF patients, respectively. This study using matched controls showed that AZM total body clearance and not the volume of distribution is higher in CF patients as a result of increased renal clearance. Pharmacokinetic parameter estimates in healthy subjects resulted in a clinical susceptibility breakpoint of ≤4 mg/liter for a dose of 1,000 mg every 8 h. Patients suspected of having high clearance rates, such as CF patients, should be monitored closely, with dosing regimens adjusted accordingly.

* Corresponding author. Mailing address: Pediatric Pharmacology Research Unit, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 6018, Cincinnati, OH 45229-3039. Phone: (513) 636-0159. Fax: (513) 636-0168. E-mail: sander.vinks{at}cchmc.org

{triangledown} Published ahead of print on 18 June 2007.

Antimicrobial Agents and Chemotherapy, September 2007, p. 3049-3055, Vol. 51, No. 9
0066-4804/07/$08.00+0     doi:10.1128/AAC.01522-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • LaPlante, K. L., Sakoulas, G. (2009). Evaluating Aztreonam and Ceftazidime Pharmacodynamics with Escherichia coli in Combination with Daptomycin, Linezolid, or Vancomycin in an In Vitro Pharmacodynamic Model. Antimicrob. Agents Chemother. 53: 4549-4555 [Abstract] [Full Text]  


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