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

Aims Experimental studies have suggested that constant intravenous infusion would be preferable to conventional intermittent bolus administration of b eta-lactam antibiotics for serious Gram-negative infections. Severe melioid osis (Burkholderia pseudomallei infection) carries a mortality of 40% despi te treatment with high dose ceftazidime. The aim of this study was to measu re the pharmacokinetic and pharmacodynamic effects of continuous infusion o f 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 perfor m estimation of pharmacokinetic and pharmacodynamic parameters. Results Of the 34 patients studied 16 (59%) died. Twenty patients had cultu res positive for B. pseudomallei of whom 12 (60%) died. The median MIC90 of B. pseudomallei was 2 mg 1(-1), giving a target concentration C-T, of 8 mg 1(-1). The median (range) estimated total apparent volume of distribution, systemic clearance and terminal elimination half-lives of ceftazidime were 0.368 (0.231-0.573) 1 kg(-1), 0.058 (0.005-0.159) 1 kg(-1) h(-1) and 7.74 (1.95-44.71) h, respectively. Clearance of ceftazidime and creatinine clear ance were correlated closely (1 =0.71; P<0.001) and there was no evidence o f si,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 conve ntional 8 h intermittent dosing to patients with normal renal function,, pl asma ceftazidime concentrations could fall below the target concentration b ut this would be unlikely with a constant infusion. Correction for renal fa ilure which is common in these patients is Clearance = k * creatinine clear ance where k=0.072. Calculation of a loading dose gives median (range) valu es of loading dose, DL of 3.7 mg kg(-1) (1.9-4.6) and infusion rate I = 0.4 6 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.