PHARMACODYNAMICS OF CEFTAZIDIME ADMINISTERED AS CONTINUOUS-INFUSION OR INTERMITTENT BOLUS ALONE AND IN COMBINATION WITH SINGLE DAILY-DOSE AMIKACIN AGAINST PSEUDOMONAS-AERUGINOSA IN AN IN-VITRO INFECTION MODEL

We compared the pharmacodynamics and killing activity of ceftazidime, administered by continuous infusion and intermittent bolus, against Pseudomonas aeruginosa ATCC 27853 and ceftazidime-resistant P. aeruginosa 27853CR with and without a single daily dose of amikacin in an in vitro infection model over a 48-h period. Resistance to ceftazidime was selected for by serial passage of P. aeruginosa onto agar containing increasing concentrations of ceftazidime. Human pharmacokinetics and dosages were simulated as follows: half-life, 2 h; intermittent-bolus ceftazidime, 2 g every 8 h (q8h) and q12h; continuous infusion, 2-g loading dose and maintenance infusions of 5, 10, and 20 mu g/ml; amikacin, 15 mg/kg q24h. There was no significant difference in time to 99.9% killing between any of the monotherapy regimens or between any combination regimen against ceftazidime susceptible P. aeruginosa. Continuous infusions of 10 and 20 mu g/ml killed as effectively as an intermittent bolus of 2 g q12h and q8h, respectively. Continuous infusion of 20 mu g/ml and an intermittent bolus of 2 g q8h were the only regimens which prevented organism regro with at 48 h, while a continuous infusion of 5 mu g/ml resulted in the most regrowth. All of the combination regimens exhibited a synergistic response, with rapid killing of ceftazidime-susceptible P. aeruginosa and no regrowth. Against ceftazidime-resistant P. aeruginosa, none of the ceftazidime monotherapy regimens achieved 99.9% killing. The combination regimens exhibited the same rapid killing of the resistant strain as occurred with the susceptible strain; however, regrowth occurred with all regimens. The combination regimens of continuous infusion of 20 mu g/ml plus amikacin and intermittent bolus q8h or q12h plus amikacin continued to be synergistic. Overall, continuous infusion monotherapy with ceftazidime at concentrations 4 to 5 and 10 to 15 times the MIC was as effective as an intermittent bolus of 2 g q12h (10 to 15 times the MIC) and q8h (25 to 35 times the MIC), respectively, against ceftazidime-susceptible P. aeruginosa, Combination therapy with amikacin plus ceftazidime, either intermittently q8h or by continuous infusion of 20 mu g/ml, appeared to be effective and exhibited synergism against ceftazidime-resistant P. aeruginosa.