Pharmacokinetics of ceftazidime in serum and suction blister fluid during continuous and intermittent infusions in healthy volunteers

Abstract

The pharmacokinetics of ceftazidime were investigated during intermittent (II) and continuous (CI) infusion in eight healthy male volunteers in a crossover fashion. The total daily dose was 75 mg/kg of body weight per 24 h in both regimens, given in three doses of 25 mg/kg/8 h (II) or 60 mg/kg/24 h with 15 mg/kg as a loading dose (CI). After the third dose (II) and during CI, serum and blister fluid samples were taken. Seven new blisters were raised for each timed sample by a suction blister technique. Blisters took 90 min to form. Samples were then taken from four blisters (A samples) and 1 h later were taken from the remaining three (B samples). The concentration of ceftazidime was determined using a high-performance liquid chromatography method. After II, the concentrations in serum immediately after infusion (t = 30 min) and 8 h after the start of the infusion were 137.9 (standard deviation [SD], 27.5) and 4.0 (SD, 0.7) ,ug/ml, respectively. The half-life at a phase (tl12G) was 9.6 min (SD, 4.6), t,/2, was 94.8 min (SD, 5.4), area under the concentration-time curve (AUC) was 285.4 ,ug-h/ml (SD,22.7), total body clearance was 0.115 liter/h-kg (SD, 0.022), and volume of distribution at steady state was 0.178 liter/kg (SD, 0.023). The blister fluid (A) samples showed a decline in concentration parallel to that of the concentrations in serum during the elimination phase with a ratio of 1:1. The tl2 of the A samples was 96.4 min (SD, 3.2). The concentration of ceftazidime in the B blister fluid samples was significantly higher (27%) than in the A samples over time. This shows that blisters may behave as a separate compartment and establishes the need to raise new blisters for each timed sample. The mean AUC/h during continuous infusion was 21.3 ,ug-h/ml (SD, 3.0). The total body clearance was 0.113 liter/h kg (SD, 0.018), the urinary clearance was 0.105 liter/h kg (SD, 0.012), and the ceftazidime/creatinine clearance ratio was 0.885. The mean AUC of blister fluid per hour was 84.5% (18.0 ,ug h/liter; SD, 3.6) compared with that of serum. The A samples did not differ significantly from the B samples. The implications of continuous infusion of beta-lactams for treatment of serious infections are discussed.Time-kill studies of beta-lactam antibiotics on aerobic gram-negative rods show a bactericidal activity which is slow, proceeds with time, and is maximal at relatively low concentrations (23). The killing is exclusively related to the time that levels in serum and tissue exceed a certain threshold, whereas higher concentrations contribute no extra effect. When levels fall below this threshold, bacterial growth is immediately resumed. This interaction of beta-lactams with gram-negative rods has consequences for the way in which these drugs should be administered. It has been shown, in experimental infections, that a continuous infusion of ceftazidime leads to better results than intermittent administration (13). This effect was most pronounced in severe infections. There are a few clinical reports that ceftazidime ...

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