title: 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.
abstract: 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 micrograms/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 micrograms/ml killed as effectively as an intermittent bolus of 2 g q12h and q8h, respectively. Continuous infusion of 20 micrograms/ml and an intermittent bolus of 2 g q8h were the only regimens which prevented organism regrowth at 48 h, while a continuous infusion of 5 micrograms/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 micrograms/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 micrograms/ml, appeared to be effective and exhibited synergism against ceftazidime-resistant P. aeruginosa.
mesh_terms: D000583:Amikacin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000627:therapeutic use; D002442:Ceftazidime / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018550:Cephalosporin Resistance; D002511:Cephalosporins / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004359:Drug Therapy, Combination / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D000583:Amikacin; D002442:Ceftazidime