Pharmacokinetic-pharmacodynamic evaluation of ceftazidime continuous infusion vs intermittent bolus injection in septicaemic melioidosis (vol 49, pg 445, 2000)

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 over 40% des pite treatment with high dose ceftazidime. The aim of this study was to mea sure 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 pharm acokinetic and pharmacodynamic parameters were compared. 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 l(-1), giving a minimum target concentration (4*M IC) of 8 mg l(-1). The median (range) estimated total apparent volume of di stribution, systemic clearance and terminal elimination half-lives of cefta zidime were 0.468 (0.241-0.573) 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 creat inine 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 conve ntional 8 h intermittent dosing to patients with normal renal function, pla sma ceftazidime concentrations could fall below the target concentration bu t this would be unlikely with a constant infusion. Correction for renal fai lure, which is common in patients with meliodosis is Clearance = k * creati nine clearance where k=0.72. Calculation of a loading dose gives median (ra nge) values of loading dose, 4 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 momo gram for adjustment in renal failure is given.