Abstract
Objective
The purpose of this study was to develop and validate a model that predicts clearance and steady-state ceftazidime concentrations during continuous infusion.
Design
This was a prospective clinical observational trial. Two models describing drug clearance during the continuous infusion of ceftazidime to infected patients were developed. The first model included inter- and intraindividual variability (IIV) while the second extended the first model by including interoccasional variability (IOV).
Setting
This was a study of patients in a US hospital between January and June 1996.
Patients and participants
The analysis included 39 patients aged >18 years with infections at various sites.
Interventions
Patients received ceftazidime as either a 1000 or 2000mg loading dose followed by a continuous infusion of 1000 to 4000 mg/day. Serum samples were collected under approximate steady-state conditions and ceftazidime concentrations were analysed using high performance liquid chromatography. The models were fitted to the data using a nonlinear mixed effects model as implemented in the NONMEM program.
Results
75 serum concentration measurements were included in the analysis. The routinely available clinical variables bodyweight, age, gender and serum creatinine were found to be statistically independent predictors of ceftazidime clearance. The IIV model was cross validated yielding a mean prediction error (with a 95% confidence interval) of −0.51 mg/L (−2.5 to 1.4 mg/L) and a mean absolute prediction error of 6.5 mg/L (5.3 to 7.8 mg/L).
Conclusion
We have developed and validated a model to estimate ceftazidime concentrations during continuous infusion using commonly available clinical information. Additional work is needed to compare outcomes of patients receiving continuous and intermittently administered ceftazidime, and to define the optimal target steady-state ceftazidime concentrations during continuous infusion.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Gentry LO. Antimicrobial activity, pharmacokinetics, therapeutic indications, and adverse reactions of ceftazidime. Pharmacotherapy 1985; 5: 254–67.
Sanford JP, Gilbert DN, Moellering RC, et al. The Sanford guide to antimicrobial therapy. Vienna: Antimicrobial Therapy Inc. 1997: 28, 44.
Craig WA, Ebert SC. Killing and regrowth of bacteria in vitro: a review. Scand J Infect Dis 1990; Suppl. 74: 63–70.
Benko AS, Cappelletty DM, Kruse JA, et al. Continuous infusion versus intermittent administration of ceftazidime in critically ill patients with suspected Gram-negative infections. Antimicrob Agents Chemother 1996; 40: 691–5.
Nicolau DP, Nightingale CH, Banevicius MA, et al. Serum bactericidal activity of ceftazidime: continuous infusion versus intermittent injections. Antimicrob Agents Chemother 1996; 40: 61–4.
Mouton JW, Hollander JG. Killing of Pseudomonas aeruginosa during continuous and intermittent infusion of ceftazidime in an in vitro pharmacokinetic model. Antimicrob Agents Chemother 1994; 38: 931–6.
Leroy A, Leguy F, Borsa F, et al. Pharmacokinetics of ceftazidime in normal and uremic subjects. Antimicrob Agents Chemother 1984; 25: 638–42.
Min-Shung L, Lee-Shing W, Jin-ding H. Single- and multiple-dose pharmacokinetics of ceftazidime in infected patients with varying degrees of renal function. J Clin Pharmacol 1989; 29: 331–7.
Ljungberg B, Nilsson-Ehle I. Influence of age on the pharmacokinetics of ceftazidime in acutely ill patients. Eur J Clin Pharmacol 1988; 34: 173–8.
Ljungberg B, Nilsson-Ehle I. Comparative pharmacokinetics of ceftazidime in young, healthy, and elderly, acutely ill males. Eur J Clin Pharmacol 1988; 34: 179–86.
Ljungberg B, Nilsson-Ehle I. Advancing age and acute infection influence the kinetics of ceftazidime. Scand J Infect Dis 1989; 21: 327–32.
Pasko MT, Beam TR, Spooner JA, et al. Safety and pharmacokinetics of ceftazidime in patients with chronic hepatic dysfunction. J Antimicrob Chemother 1985; 15: 365–74.
Alestig K, Trollfors B, Andersson R, et al. Ceftazidime and renal function. J Antimicrob Chemother 1984; 13: 177–81.
Walstad RA, Dahl K, Helium KB, et al. The pharmacokinetics of ceftazidime in patients with impaired renal function and concurrent frusemide therapy. Eur J Clin Pharmacol 1988; 35: 273–9.
Walstad RA, Aanderud L, Thurmann-Nielsen E. The pharmacokinetics and tissue concentrations of ceftazidime in burn patients. Eur J Clin Pharmacol 1988; 35: 543–9.
Ohkawa M, Nakashima T, Shoda R, et al. Pharmacokinetics of ceftazidime in patients with renal insufficiency and in those undergoing hemodialysis. Chemotherapy 1985; 31: 410–6.
Norrby SR, Burman LA, Linderholm H, et al. Ceftazidime: pharmacokinetics in patients and effects on the renal function. J Antimicrob Chemother 1982; 10: 199–206.
Warns H, Lode H, Harnoss CM, et al. Multiple dose pharmacokinetics and therapeutic results with ceftazidime. J Antimicrob Chemother 1983; 12: 235–40.
Hoffler D, Koeppe P, Williams KJ. The pharmacokinetics of ceftazidime in normal and impaired renal function. J Antimicrob Chemother 1983; 12: 241–5.
Naber KG, Kees F, Grobecker H. Ceftazidime: pharmacokinetics in young volunteers versus elderly patients and therapeutic efficacy with complicated urinary tract infections. J Antimicrob Chemother 1983; 12: 41–5.
Kercsmar CM, Stern RC, Reed MD, et al. Ceftazidime in cystic fibrosis: pharmacokinetics and therapeutic response. J Antimicrob Chemother 1983; 12: 289–95.
Young RJ, Lipman J, Gin T, et al. Intermittent bolus dosing of ceftazidime in critically ill patients. J Antimicrob Chemother 1997; 40: 269–73.
Garcia I, Fainstein V, Smith RG, et al. Multiple-dose pharmacokinetics of ceftazidime in cancer patients. Antimicrob Agents Chemother 1983; 24 (2): 141–4.
Ackerman BH, Ross J, Tofte RW, et al. Effects of decreased renal function on the pharmacokinetics of ceftazidime. Antimicrob Agents Chemother 1984; 25: 785–6.
Welage LS, Schultz RW, Schentag JJ. Pharmacokinetics of ceftazidime in patients with renal insufficiency. Antimicrob Agents Chemother 1984; 25: 201–4.
Sommers DK, Walters L, Van Wyk M, et al. Pharmacokinetics of ceftazidime in male and female volunteers. Antimicrob Agents Chemother 1983; 23: 892–6.
Kashuba ADM, Ballow CH, Forrest A. Development and evaluation of a bayesian pharmacokinetic estimator and optimal, sparse sampling strategies for ceftazidime. Antimicrob Agents Chemother 1996; 40: 1860–5.
Hedman A, Adan-Abdi Y, Alvan G, et al. Influence of glomerular filtration rate on renal clearance of ceftazidime in cystic fibrosis. Clin Pharmacokinet 1988; 15: 57–65.
Vinks AATMM, Mouton JW, Touw DJ, et al. Population pharmacokinetics of ceftazidime in cystic fibrosis patients analyzed by using a nonparametric algorithm and optimal sampling strategy. Antimicrob Agents Chemother 1996; 40: 1091–7.
Mouton JW, Vinks AATMM, Punt NC. Pharmacokinetic-pharmacodynamic modeling of activity of ceftazidime during continuous and intermittent infusion. Antimicrob Agents Chemother 1997; 41: 733–8.
Mandura M, Mihm LB, White RL, et al. Comparative bactericidal activity of ceftazidime against isolates of Pseudomonas aeruginosa as assessed in an in vitro pharmacodynamic model versus the traditional time-kill method. Antimicrob Agents Chemother 1997; 41: 2527–32.
Beal SL, Sheiner LB, editors. NONMEM users guides. San Francisco: NONMEM Project Group, University of California at San Francisco, 1992.
Standards for antimicrobial susceptibility testing; eighth informational supplement. Wayne (PA): National Committee for Clinical Laboratory Standards, 1998: 10.
Beal SL, Sheiner LB. NONMEM users guide VTI: conditional estimation methods. San Francisco: NONMEM Project Group, University of California at San Francisco, 1997.
Karlsson MO, Sheiner LB. The importance of modeling interoccasion variability in population pharmacokinetic analysis. J Pharmacokinet Biopharmaceut 1993; 21: 735–50.
Davison AC. Bootstrap methods and their application. New York: Cambridge University Press, 1997.
Bertino JS. Measured versus estimated creatinine clearance in patients with low serum creatinine values. Ann Pharmacother 1993; 27: 1439–41.
Smythe M, Hoffman J, Kizy K, et al. Estimating creatinine clearance in elderly patients with low serum creatinine concentrations. Am J Hosp Pharm 1994; 51: 198–204.
Facca BF, Frame B, Treisenberg S. Population pharmacokinetics of ceftizoxime administered by continuous infusion in clinically ill adult patients. Antimicrob Agents Chemother 1998; 42: 1783–7.
Craig WA. The rationale for continuous-infusion dosing of betalactams. Infect Med 1992; Suppl. 9: 6–9.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Frame, B.C., Facca, B.F., Nicolau, D.P. et al. Population Pharmacokinetics of Continuous Infusion Ceftazidime. Clin Pharmacokinet 37, 343–350 (1999). https://doi.org/10.2165/00003088-199937040-00005
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003088-199937040-00005