Pharmacokinetics of cephalosporins in normal and septicemic rabbits

Abstract

The differences in the pharmacokinetics of cefotaxime, moxalactam, and CPW 86-363, a new expandedspectrum cephalosporin, were studied in healthy rabbits and in rabbits infected intravenously with Streptococcus pneumoniae. The pharmacokinetic analysis of concentration-time courses in the sera of infected animals according to a two compartment-model evidenced a clear decrease of drug fractions in the central compartment but enhanced drug fractions in the peripheral compartment. The shift was more pronounced in animals which received CPW 86-363 (60%; P < 0.05) than in those which received cefotaxime (20%) or moxalactam (5%). Corresponding increases in drug concentration were observed in soft tissue interstitial fluid; therefore, the areas under the curve and mean residence times in the soft tissue interstitial fluid of infected rabbits were prolonged. The shift of drug fractions from the central compartment to other body fluid compartments during infection was thought to be due to cardiovascular changes associated with fever. No changes in serum binding of the three drugs were found during the course of the infection. The quantitative differences in the extent of altered distribution properties of the drugs might be due to variations in the physicochemical properties of the drugs.The pharmacokinetics of various antibiotics have been extensively studied in healthy individuals and in patients with various degrees of renal or hepatic impairment. Only limited information, however, on the pharmacokinetics of antibiotics in patients or experimental animals with septicemia is available (2, 13). It might be anticipated that during such a severe pathological condition, the altered blood flow and permeability of blood vessel walls would influence the pharmacokinetics of antibiotics. Recent results indicate that during experimental meningitis in rabbits, the volume of distribution is larger than that in healthy rabbits (10). Hence, the concentrations of cefoperazone, moxalactam, and cefotaxime in the sera of infected rabbits are lower than those in the sera of healthy rabbits. We therefore studied the influence of septicemia on the pharmacokinetics of three expanded-spectrum cephalosporins, cefotaxime, moxalactam, and CPW 86-363, by monitoring their concentrations in serum and in the fluid of subcutaneously implanted diffusion chambers. MATERIALS AND METHODSIn each set of experiments, one group of four healthy and one group of four infected male chinchilla rabbits (weight, 3.0 to 3.5 kg each) were used. were obtained from a marginal ear vein of each rabbit before and at 5, 15, and 30 min and 1, 2, 3, and 4 h after drug administration. In addition, viable bacteria were estimated from blood samples drawn at 1, 2, 5, 6, 8, and 15 h after the inoculation and at the same time as blood was sampled for pharmacokinetic analysis.In each rabbit, six diffusion chambers filled with physiological saline were implanted subcutaneously in the back 3 days before the study, by the procedure of Laber et al. (8). These chambers consist of filter...

Animal Models ofStreptococcus pneumoniaeDisease

“…Finally, an i.v. model of sepsis was established in chinchilla rabbits to study the pharmacokinetics of cephalosporins (82).…”

Influence of Fever on Cefazolin Pharmacokinetics

“…The pharmacokinetics of cefazolin was studied in rats, and a decreased total Cl was observed as well 19 . Larger volumes of distribution and a higher Cl were observed during fever in the previously mentioned studies on other cephalosporins 10,11,16 .…”

“…Lower V 1 values were found in the subgroup of patients in whom a two-compartment model best fitted to the measured serum concentrations. Although different volumes of distribution were calculated in different studies, enlargement of the volumes during fever was reported in most studies on the pharmacokinetics of beta-lactam antibiotics, aminoglycosides and trimethoprim 10,11,[16][17][18][19][20][21] . Smaller V 1 during fever was only found for sulphadimidin in dogs and tobramycin in rats 22,23 .…”

Quantification of tissue distribution of antibiotics by kinetic hysteresis analysis

“…Healthy rabbits were injected with cefotaxime 10, 15, 30, 50, 60 and 100 mg/kg body weight [Ganzinger and Haslberger 1985;Ganzinger et al 1986 a, b;Haslberger et al 1987]. Eq.3 was used to calculate the areas of the hysteresis loops (AROHYL) in individual animals and in each dosage group (four animals per group) by population pharmacokinetic analysis.…”

“…The methods used in these experiments, such as dosage, route of application, time of sampling from serum and interstitial fluid in implanted tissue cages etc, have previously been published [Ganzinger and Haslberger 1985;Ganzinger et al 1986 a, b;Haslberger et al 1987]. Pharmacokinetic parameters were calculated using the PttARM program both for individual values and population parameters [Gomeni t984].…”