Simulation of human pharmacokinetic profiles in mice, and impact on antimicrobial efficacy of netilmicin, ticarcillin and ceftazidime in the peritonitis-septicemia model.
Pharmacokinetic profiles in small animals substantially differ from those observed in man. We hence devised a man adapted animal model to critically assess the impact of such differences on antimicrobial efficacy. We approximated in mice the human pharmacokinetic profiles of netilmicin, ticarcillin and ceftazidime. The CD50 (curative dose for 50% of lethally intra-peritoneally infected animals) against Pseudomonas aeruginosa was comparatively determined for murine versus man-adapted pharmacokinetic profiles. With netilmicin the man-adapted profile was significantly less efficacious than the murine profile. In contrast, a significant superiority of the man-adapted profile was found with the beta-lactam drugs. We conclude that determinations of antimicrobial activity in small animals may yield misleading results in respect to man. Depending on the drug in question, murine pharmacokinetics may lead to overestimation or underestimation of antimicrobial activity. Our findings are of particular importance for the interpretation of studies in small animals comparing different antimicrobial compounds or different dosage regimens.
Gerber
A U
AU
Division of Medicine, Regionalspital Burgdorf, Switzerland.
Stritzko
T
T
Segessenmann
C
C
Stalder
B
B
D000818:Animals; D002442:Ceftazidime / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005260:Female; D006207:Half-Life; D007279:Injections, Subcutaneous; D051379:Mice; D008813:Mice, Inbred ICR; D009428:Netilmicin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010538:Peritonitis / Q000188:drug therapy*; D011552:Pseudomonas Infections / Q000188:drug therapy; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D011897:Random Allocation; D018805:Sepsis / Q000188:drug therapy*; D013047:Specific Pathogen-Free Organisms; D013982:Ticarcillin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use
D009428:Netilmicin; D002442:Ceftazidime; D013982:Ticarcillin