Current addresses: Public Health Laboratory, Taunton & Somerset Hospital, Taunton, United Kingdom. †Wellcome Unit, Queen Elizabeth Hospital, Blantyre, Malawi.
Pharmacokinetic-pharmacodynamic evaluation of ceftazidime continuous infusion vs intermittent bolus injection in septicaemic melioidosis
Article first published online: 5 APR 2002
British Journal of Clinical Pharmacology
Volume 49, Issue 5, pages 445–452, May 2000
How to Cite
Angus, B. J., Smith, M. D., Suputtamongkol, Y., Mattie, H., Walsh, A. L., Wuthiekanun, V., Chaowagul, W. and White, N. J. (2000), Pharmacokinetic-pharmacodynamic evaluation of ceftazidime continuous infusion vs intermittent bolus injection in septicaemic melioidosis. British Journal of Clinical Pharmacology, 49: 445–452. doi: 10.1046/j.1365-2125.2000.00179.x
- Issue published online: 5 APR 2002
- Article first published online: 5 APR 2002
- Received 11 May 1999, accepted 4 January 2000.
- Burkholderia pseudomallei;
- continuous infusion;
- melioidosis therapy;
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.