An effort was made to elucidate the limits of drug-activity tests in small animals. Human plasma kinetics of gentamicin, netilmicin, ticarcillin, ceftazidime, and ceftriaxone were approximated in normal and in granulocytopenic mice infected with various strains of Pseudomonas aeruginosa in the thigh muscle or intraperitoneally. The effect of such dosing on bacterial time-kill curves and on survival was compared with the effect of identical amounts of drug given as a single-bolus injection. With fl-lactams, a highly significant superiority of fractionated dosing (simulated human kinetics) over bolus injections (murine plasma kinetics) was demonstrated, whereas with aminoglycosides it was a singlebolus injection that tended to be more active. Thus, when tested in conventional smallanimal models, aminoglycoside activity may be overestimated, whereas fl-lactam activity may be underestimated in respect to humans. These differences found in vivo most probably reflect the different pharmacodynamics between aminoglycosides and f3-lactam drugs (time-kill curves, dose-response curves, and postantibiotic effect) similar to those previously observed in vitro.In a first approach, the in vivo activity and toxicity of any new drug is routinely studied in experimental models by using small animals such as mice, rats, guinea pigs, or rabbits. Moreover, some measure of the activity and toxicity of a single dose has become a mandatory requirement for any new drug to be licensed. Although conclusions from such studies are not directly transferable to man, they are at least looked on as a basis for investigations to be performed in more expensive animal models or humans. However, major biologic differences have to be considered between small experimental animals and man, one of which is metabolic activity in general. This difference becomes most evident in a compari- The present study was based on the hypothesis that the difference between small animals and man regarding drug kinetics cannot be overcome by just injecting larger amounts (per kilogram of body weight) of that substance into small animals. Rather, some kind of "human-adapted" pharmacokinetics of the study drug should be approximated in small animals.In a tentative pioneering effort we used an experimental thigh infection -as well as the standard mouse peritonitis model -to elucidate the impact of murine vs. human half-life of J3-lactam drugs and aminoglycosides on activity against Pseudomonas aeruginosa. In one group of mice the study drug was given as a single-bolus injection that was followed 90

The influence of dosing intervals on the activity of gentamicin and ticarcillin againstPseudomonas aeruginosa was studied in vivo. Granulocytopenic mice infected with P. aeruginosa in the thigh muscle were treated with l-hr or 3-hr injections of gentamicin, ticarcillin, or gentamicin-ticarcillin. Plasma pharmacokinetics of the drugs were correlated with antibacterial activity. Gentamicin injected every 1 hr tended to be less active than gentamicin injected at longer intervals. In contrast, ticarcillin given every 1 hr was significantly more efficacious than equivalent total doses injected every 3 hr. The dosing schedule of gentamicin-ticarcillin was again important for ticarcillin but did not appreciably affect the antibacterial activity of gentamicin. Thus, antimicrobial chemotherapy of P. aeruginosa infections in the granulocytopenic host might be improved by administering ticarcillin rather than gentamicin as a constant infusion.The optimal antibiotic treatment of gram-negative bacterial infections in granulocytopenic patients remains an unsolved clinical problem, particularly for infections due to Pseudomonas aeruginosa, although progress has been made by combining antipseudomonal drugs and by using doses approaching toxic levels. Additional progress could possibly be made by finding optimal dosing schedules for these drugs. This aspect of antimicrobial chemotherapy has hardly been investigated. In some recent clinical trials aminoglycoside antibiotics were administered as constant infusions [1][2][3]. Although it was concluded that such infusions might be more effective than intermittent dosing, the results supporting this conclusion were not significant. In vitro, no superiority could be demonstrated for constant infusions vs, intermittent doses of gentamicin against P. aeru-

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Serum T3, T4, and rT3 levels as well as liver nuclear T3 receptors (NT3R) were measured in mice with a bacterial infection. Pseudomonas aeruginosa were injected into one thigh of ICR mice, resulting in a severe infection at sacrifice 15 h later. Since food intake, which influences serum thyroid hormone levels and NT3R, was 75% lower in infected than in control mice, infected mice were either fed and compared with pair-fed controls or fasted and compared with fasted and fed controls. Fasting induced a fall in serum T3 and T4 levels, which was even more pronounced in infected fasted animals. However, while fasting caused an approximately 80% increase in serum rT3 concentrations, serum rT3 levels in infected fasted animals were not different from those in fed controls. The combination of infection and fasting thus prevented the rise in serum rT3 otherwise invariably associated with fasting. NT3R measurements on isolated nuclei revealed the presence of NT3R in mouse liver similar to those reported in rat liver. The NT3R Kd (approximately 2 X 10(-10) M) was not affected by decreased food intake, infection, or a combination thereof. The NT3R maximum binding capacity (MBC) was decreased in fasted animals (460 vs. 306 pg/mg DNA). However, the MBC of infected fasted mice was not different from that of fasted mice. Similarly, no difference in MBC was found between infected fed and pair-fed control mice. In mice injected with heat-killed P. aeruginosa to evaluate potential effects of endotoxins, neither serum thyroid hormone levels nor hepatic NT3R were different from those of controls. These data show that in mice, a severe bacterial infection with P. aeruginosa has effects on serum hormone levels not explained by the disease-associated diminished food intake, whereas it has no effects on liver NT3R beyond those due to the disease-related decreased food intake.