CONTINUOUS-INFUSION VERSUS INTERMITTENT ADMINISTRATION OF CEFTAZIDIMEIN CRITICALLY ILL PATIENTS WITH SUSPECTED GRAM-NEGATIVE INFECTIONS

The pharmacodynamics and pharmacokinetics of ceftazidime administered by continuous infusion and intermittent bolus over a 4-day period were compared. We conducted a prospective, randomized, crossover study of 12 critically ill patients with suspected gram-negative infections. Th e patients were randomized to receive ceftazidime either as a 2-g intr avenous (i.v.) loading dose followed by a 3-g continuous infusion (CI) over 24 h or as 2 g i.v. every 8 h (q8h), each for 2 days. After 2 da ys, the patients were crossed over and received the opposite regimen. Each regimen also included tobramycin (4 to 7 mg/kg of body weight, gi ven i.v. q24h). Eighteen blood samples were drawn on study days 2 and 4 to evaluate the pharmacokinetics of ceftazidime and its pharmacodyna mics against a clinical isolate of Pseudomonas aeruginosa (R288). The patient demographics (means a standard deviations) were as follows: ag e, 57 +/- 12 years; sex, nine males and three females; APACHE II score , 15 +/- 3; diagnosis, 9 of 12 patients with pneumonia. The mean pharm acokinetic parameters for ceftazidime given as an intermittent bolus ( IB) (means cc standard deviations) were as follows: maximum concentrat ion of drug in serum, 124.4 +/- 52.6 mu g/ml; minimum concentration in serum, 25.0 +/- 17.5 mu g/ml; elimination constant, 0.268 +/- 0.205 h (-1); half-life, 1.61 h; and volume of distribution, 18.9 +/- 9.0 lite rs. The steady-state ceftazidime concentration for CI was 29.7 +/- 17. 3 mu g/ml, which was not significantly different from the targeted con centrations. The range of mean steady-state ceftazidime concentrations for the 12 patients was 10.6 to 62.4 mu g/ml. Tobramycin peak concent rations ranged between 7 and 20 mu g/ml. As expected, the area under t he curve for the 2-g q8h regimen was larger than that for CI (P = 0.00 3). For IB and CI, the times that the serum drug concentration was gre ater than the MIC were 92 and 100%, respectively, for each regimen aga inst the P. aeruginosa clinical isolate. The 24-h bactericidal titers in serum, at which the tobramycin concentrations were <1.0 mu g/ml in all patients, were the same for CI and IB (1:4). In the presence of to bramycin, the area under the bactericidal titer-time curve (AUBC) was significantly greater for IB than CI (P = 0.001). After tobramycin was removed from the serum, no significant difference existed between the AUBCs for CI and IB. We conclude that CI of ceftazidime utilizing one -half the IB daily dose was equivalent to the IB treatment as judged b y pharmacodynamic analysis of critically ill patients with suspected g ramnegative infections. No evaluation comparing the clinical efficacie s of these two dosage regimens was performed.