Comparison of amikacin dosing regimens in neutropenic guinea pigs with Escherichia coli infection

Abstract

Objective - To derive pharmacokinetic data for 3 amikacin dosing regimens in guinea pigs and to determine whether the antibacterial activity of 15 mg/kg of body weight given twice daily is equivalent to administering the drug more frequently. Animals - 10 guinea pigs in pharmacokinetic trials, and 10 guinea pigs in pretreatment, control, and amikacin treatment groups. Procedure - Amikacin pharmacokinetic data were determined in guinea pigs after single IM administration of 3.75, 7.5, and 15 mg/kg. Guinea pigs had been made neutropenic by treatment with cyclophosphamide. All guinea pigs were inoculated with 2.8 x 108 colony-forming units (CFU) of Escherichia coli in the thigh muscle, then were allotted to 5 groups: pretreatment (euthanatized 4 hours after inoculation), control, and 3 amikacin treatment groups (3.75 mg/kg, q 3 h; 7.5 mg/kg, q 6 h; and 15 mg/kg, q 12 h). Amikacin administration was begun 4 hours after E coli inoculation and was continued for 72 hours. Numbers of E coli CFU in infected thigh muscle were determined for each guinea pig. Results - Difference in survival between control and the amikacin-treated groups was significant. The E coli infection concentration (log10 CFU) increased significantly in the control, compared with the pretreatment, group. Infection concentration decreased significantly in all treatment groups, compared with the pretreatment group. There was no significant difference in bacterial killing among the 3 treatment groups. Conclusion - Amikacin had a significant effect on survival of neutropenic guinea pigs with E coli infection. Antibacterial did not differ among 3 doses of amikacin and administered at difference intervals. Clinical Relevance - Aminoglycoside dosing regimen with high peak concentration and long drug- free interval is as efficacious as divided dose regimens.