Pharmacokinetics of ceftazidime in patients with liver cirrhosis and ascites

Aim The aim of this study was to characterize, via a population pharmacokinetic approach, the pharmacokinetics of ceftazidime in burn patients who were not in the acute post-injury phase. Methods The development of the pharmacokinetic model was based on data from therapeutic drug monitoring (41 patients, 94 samples). The estimation of population pharmacokinetic parameters and the selection of covariates (age, gender, body weight, size of burn and creatinine plasma concentration) that could affect the pharmacokinetics were performed with a nonlinear mixed effect modelling method. Results No relationship between covariates and the pharmacokinetic parameters was established with the exception of an inverse-linear relationship between creatinine plasma concentration and ceftazidime total clearance. The total clearance of ceftazidime was 2.72 l h -1 [coefficient variation (CV) = 56.3%] and the distribution volume of the central compartment was 0.28 l kg -1 (CV = 13.2%) The transfer rate constants (k12, k 21) between the central and peripheral compartments were 0.06718 h -1 (CV = 87.2%) and 0.001823 h -1 (CV = 82.7%), respectively. From these parameters, the total ceftazidime volume of distribution (10.64 l kg -1 ) was calculated. Conclusion The population parameters were different from those obtained in a previous study performed in fewer patients and in the early period after burn injury. In our study, the lower ceftazidime clearance could be explained by the relative decrease in ceftazidime elimination in relation to the burn area, and the higher ceftazidime volume of distribution in the presence of interstitial oedema, which could act as a reservoir from which ceftazidime returns slowly to the circulation.

Section: Figuresupporting

confidence: 78%

Population pharmacokinetics of ceftazidime in burn patients

Dailly

Pannier²,

Jolliet

et al. 2003

“…Approximately 1% of ceftazidime clearance is through biliary excretion. Previous studies in chronic liver failure and in cirrhosis have shown changes in volume of distribution resulting in shortened elimination half-times with no overall change in total body clearance [35,36]. There was no evidence for signi®cant nonrenal clearance in this study [37].…”

Section: Discussioncontrasting

confidence: 44%

Pharmacokinetic‐pharmacodynamic evaluation of ceftazidime continuous infusion vs intermittent bolus injection in septicaemic melioidosis

Angus

Smith

Suputtamongkol

et al. 2000

Aims Experimental studies have suggested that constant intravenous infusion would be preferable to conventional intermittent bolus administration of beta‐lactam antibiotics for serious Gram‐negative infections. Severe melioidosis (Burkholderia pseudomallei infection) carries a mortality of 40% despite treatment with high dose ceftazidime. The aim of this study was to measure the pharmacokinetic and pharmacodynamic effects of continuous infusion of ceftazidime vs intermittent bolus dosing in septicaemic melioidosis. Methods Patients with suspected septicaemic melioidosis were randomised to receive ceftazidime 40 mg kg−1 8 hourly by bolus injection or 4 mg kg−1 h−1 by constant infusion following a 12 mg kg−1 priming dose to perform estimation of pharmacokinetic and pharmacodynamic parameters. Results Of the 34 patients studied 16 (59%) died. Twenty patients had cultures positive for B. pseudomallei of whom 12 (60%) died. The median MIC90 of B. pseudomallei was 2 mg l−1, giving a target concentration CT, of 8 mg l−1. The median (range) estimated total apparent volume of distribution, systemic clearance and terminal elimination half‐lives of ceftazidime were 0.468 (0.241–0.573) l kg−1, 0.058 (0.005–0.159) l kg−1 h−1 and 7.74 (1.95–44.71) h, respectively. Clearance of ceftazidime and creatinine clearance were correlated closely (r = 0.71; P < 0.001) and there was no evidence of significant nonrenal clearance. Conclusions Simulations based on these data and the ceftazidime sensitivity of the B. pseudomallei isolates indicated that administration by constant infusion would allow significant dose reduction and cost saving. With conventional 8 h intermittent dosing to patients with normal renal function, plasma ceftazidime concentrations could fall below the target concentration but this would be unlikely with a constant infusion. Correction for renal failure which is common in these patients is Clearance =k* creatinine clearance where k = 0.072. Calculation of a loading dose gives median (range) values of loading dose, DL of 3.7 mg kg−1 (1.9–4.6) and infusion rate I = 0.46 mg kg h−1 (0.04–1.3) (which equals 14.8 mg kg−1 day−1). A nomogram for adjustment in renal failure is given.

“…Approximately 1% of ceftazidime clearance is through biliary excretion. Previous studies in chronic liver failure and in cirrhosis have shown changes in volume of distribution resulting in shortened elimination half‐times with no overall change in total body clearance [35, 36]. There was no evidence for significant nonrenal clearance in this study [37].…”

Section: Discussionmentioning

confidence: 45%

Pharmacokinetic‐pharmacodynamic evaluation of ceftazidime continuous infusion vs intermittent bolus injection in septicaemic melioidosis

Angus

Smith

Suputtamongkol

et al. 2000

Aims Experimental studies have suggested that constant intravenous infusion would be preferable to conventional intermittent bolus administration of beta‐lactam antibiotics for serious Gram‐negative infections. Severe melioidosis (Burkholderia pseudomallei infection) carries a mortality over 40% despite treatment with high dose ceftazidime. The aim of this study was to measure the pharmacokinetic and pharmacodynamic effects of continuous infusion of ceftazidime vs intermittent bolus dosing in septicaemic melioidosis.Methods Patients with suspected septicaemic melioidosis were randomised to receive ceftazidime 40 mg kg−1 8 hourly by bolus injection or 4 mg kg−1 h−1 by constant infusion following a 12 mg kg−1 priming dose and pharmacokinetic and pharmacodynamic parameters were compared.Results Of the 34 patients studied 16 (59%) died. Twenty patients had cultures positive for B. pseudomallei of whom 12 (60%) died. The median MIC90 of B. pseudomallei was 2 mg l−1, giving a minimum target concentration (4*MIC) of 8 mg l−1. The median (range) estimated total apparent volume of distribution, systemic clearance and terminal elimination half‐lives of ceftazidime were 0.468 (0.241–0.573) l kg−1, 0.058 (0.005–0.159) l kg−1 h−1 and 7.74 (1.95–44.71) h, respectively. Clearance of ceftazidime and creatinine clearance were correlated closely (r = 0.71; P < 0.001) and there was no evidence of significant nonrenal clearance.Conclusions Simulations based on these data and the ceftazidime sensitivity of the B. pseudomallei isolates indicated that administration by constant infusion would allow significant dose reduction and cost saving. With conventional 8 h intermittent dosing to patients with normal renal function, plasma ceftazidime concentrations could fall below the target concentration but this would be unlikely with a constant infusion. Correction for renal failure, which is common in patients with meliodosis is Clearance =k* creatinine clearance where k = 0.72. Calculation of a loading dose gives median (range) values of loading dose, DL of 18.7 mg kg−1 (9.5–23) and infusion rate I = 3.5 mg kg−1 h−1 (0.4–13) (which equals 84 mg kg−1 day−1). A nomogram for adjustment in renal failure is given.