Pharmacokinetic-pharmacodynamic modeling of activity of ceftazidime during continuous and intermittent infusion

Abstract

We developed and applied pharmacokinetic-pharmacodynamic (PK-PD) models to characterize in vitro bacterial rate of killing as a function of ceftazidime concentrations over time. For PK-PD modeling, data obtained during continuous and intermittent infusion of ceftazidime in Pseudomonas aeruginosa killing experiments with an in vitro pharmacokinetic model were used. The basic PK-PD model was a maximum-effect model which described the number of viable bacteria (N) as a function of the growth rate (lambda) and killing rate (epsilon) according to the equation dN/dt = [lambda - epsilon x [Cgamma(EC50gamma + Cgamma)]] N, where gamma is the Hill factor, C is the concentration of antibiotic, and EC50 is the concentration of antibiotic at which 50% of the maximum effect is obtained. Next, four different models with increasing complexity were analyzed by using the EDSIM program (MediWare, Groningen, The Netherlands). These models incorporated either an adaptation rate factor and a maximum number of bacteria (Nmax) factor or combinations of the two parameters. In addition, a two-population model was evaluated. Model discrimination was by Akaike's information criterion. The experimental data were best described by the model which included an Nmax term and a rate term for adaptation for a period up to 36 h. The absolute values for maximal growth rate and killing rate in this model were different from those in the original experiment, but net growth rates were comparable. It is concluded that the derived models can describe bacterial growth and killing in the presence of antibiotic concentrations mimicking human pharmacokinetics. Application of these models will eventually provide us with parameters which can be used for further dosage optimization.

Low cefpirome levels during twice daily dosing in critically ill septic patients: pharmacokinetic modelling calls for more frequent dosing

“…Pharmacokinetic modelling can be used to simulate alternate dosing regimens and help identify those regimens that may yield improved plasma levels including higher troughs [20,21,22,36]. Two-compartment models have been used to describe cefpirome pharmacokinetics previously [31], and the model developed here for each patient agrees well with the measured data, as demonstrated by a comparison of model-predicted versus measured concentrations for profile A.…”

“…The above data support the concept of administering b-lactams in a way that maintains a constant plasma concentration above the required threshold while eliminating peaks and troughs. Pharmacokineticpharmacodynamic modelling using different bacterial growth models for optimising dosage regimens also support a loading dose and infusion regimen, provided concentrations greater than the required threshold are achieved [36].…”

Therapeutic drug monitoring of β-lactams in critically ill patients: proof of concept

“…Further to this, emerging in vitro findings suggest that ␤-lactam concentrations should be maintained at up to 6× the minimum inhibitory concentration (MIC) to prevent the emergence of resistance [19]. Given that in most situations bacterial re-growth will occur as soon as the ␤-lactam concentration falls below the MIC [6,[20][21][22][23] and that maximal bactericidal activity is reported to occur at concentrations of 4-5× MIC [24][25][26][27], a pharmacodynamic target of 100% fT >4-5× MIC (trough concentrations at 4-5× the concentration of the MIC of the known or suspected pathogen) was arbitrarily chosen to maximise the likelihood of clinical cure in this critically ill population. It was also considered that reduced antibiotic penetration into tissues in critically ill patients, such as those with sepsis and septic shock [9][10][11], meant that higher blood concentrations would increase the likelihood of effective antibiotic concentrations in tissue, which may be significant given that most infections occur in tissue sites [28].…”

In vivo efficacy of humanised intermittent versus continuous ceftazidime in combination with tobramycin in an experimental model of pseudomonal pneumonia

“…And (ii), the human equivalent of continuous infusion (cCAZ) at a daily dose of 4 g. For this method of delivery the target concentration of serum CAZ was ca. 30 mg/L [19,20] (the administered daily dose was 200 mg/kg/day).…”