Single, Large, Daily Dosing Versus Intermittent Dosing of Tobramycin for Treating Experimental Pseudomonas Pneumonia

Abstract

Single, large, daily aminoglycoside doses in animals are less toxic than conventional dosing, and higher drug concentrations in vitro produce more-rapid bacterial killing. Thus, we compared various aminoglycoside dosing schedules in neutropenic (n = 153) and nonneutropenic (n = 192) guinea pigs with Pseudomonas aeruginosa pneumonia. Equivalent tobramycin dosages were given: 5 mg/kg every 4 h or 30 mg/kg every 24 h. Animals were serially killed during therapy, and quantitative lung cultures were performed. Bacterial titers in lungs dropped rapidly in all tobramycin-treated animals, both neutropenic and nonneutropenic, during the initial 16 h of therapy. In nonneutropenic guinea pigs, lung titers remained constant despite continued 4-h dosing. With subsequent 24-h dosing, titers continued to drop, and by 72 h there were a significant number of animals with sterile lungs (P less than .01). In neutropenic guinea pigs given tobramycin every 24 h, bacterial regrowth occurred; thus, therapy was ineffective. Adding mezlocillin, however, suppressed regrowth; thus, combination therapy was superior (P less than .05).