Distribution of Antimicrobial Agents in Normal and Diseased Animals

Abstract

SUMMARY Antimicrobial agents are distributed throughout the body by the circulating blood and must reach the focus of infection to exert their action; the majority are excreted unchanged in the urine. Extensive (> 80%) binding to serum proteins (mainly albumin) reduces the fraction of drug which is free in the serum and which consequently is available to enter other tissues. It may either hinder or facilitate elimination, depending on the mechanism of the process. Lipid solubility is the principal physicochemical property of an antimicrobial agent which influences the pattern and extent of distribution, as well as the rate of elimination. Abnormal pH reaction of extracellular fluid can, by changing degree of ionization, alter drug distribution. When comparing the apparent volume of distribution of a drug between normal and diseased animals, the apparent steady-state distribution volume (V d(ss) ) is the only meaningful term as it is independent of elimination processes. This term may be considered in conjunction with the apparent volume of the central compartment (V c ) and the individual rate constants (k 12 , k 21 , k el ) of the pharmacokinetic model. When renal function is impaired, elimination of drugs which are excreted mainly by the kidneys is decreased. This necessitates an appropriate adjustment of the dosage regimen. Reduced serum protein binding (mostly organic acids), resulting from hypoalbuminemia (nephrotic syndrome) or the uremic state (chronic renal failure), will increase the free, unbound fraction of drug that is available for extravascular distribution. Based on limited evidence, it appears that fever increases the steady-state distribution volume of antimicrobial agents without changing the apparent volume of the central compartment and the total body plasma clearance. The increased distribution volume associated with the febrile response might be attributed to an enhanced capacity to penetrate cellular barriers. It may be tentatively concluded that the response to therapy, which depends on an effective concentration of drug being achieved and maintained at the focus of infection, should be favorably influenced by the febrile state.