To predict the anti-mutant effects of antibiotic combinations against Staphylococcus aureus, the mutant prevention concentrations (MPCs) of linezolid and daptomycin were determined at a linezolid-to-daptomycin concentration ratio that corresponds to the ratio of the 24-hour areas under the concentration-time curve (AUC24s) that were used in pharmacokinetic simulations in an in vitro dynamic model. The enrichment of linezolid-resistant mutants of two S.aureus strains was observed under linezolid exposure. The growth of daptomycin-resistant mutants exposed to daptomycin was less pronounced. Combination therapy prevented or restricted the development of S.aureus resistance to linezolid or daptomycin, respectively. These findings support the applicability of MPC determination to predict the anti-mutant effects of combination therapy with linezolid and daptomycin.

The pharmacokinetics of N-(5-oxynicotinoyl)-L-glutamate (ONG) was studied in rats (doses, 20, 100 and 500 mg/kg) and rabbits (50 mg/kg) after bolus administration of calcium salt of N-(5-oxynicotinoyl)-L-glutamic acid (Ampasse preparation). The ONG concentration in the blood serum was determined by HPLC assay with fluorimetric detection. The lower limit of accurate detection for ONG was 100 ng/ml. The ONG pharmacokinetics in rats was linear at relatively small doses (20 - 100 mg/kg) but nonlinear at a large dose (500 mg/kg). The ONG concentration decay had a two-phase character in both rats and rabbits, so that the pharmacokinetic profiles were fitted to a biexponential equation of the two-compartment model. Systemic pharmacokinetic parameters determined in rats and rabbits, respectively, were as follows: total clearance, 18 and 15 ml/(min kg); steady state distribution volume, 330 and 880 ml/kg; mean retention time, 0.3 and 1.0 h; half-life, 0.73 and 2.3 h. Using the allometric approach to the interspecies extrapolation of the pharmacokinetic data, the half-life of ONG in humans is predicted to be 4 h.

The pharmacokinetics of N-(5-oxynicotinoyl)-L-glutamate (ONG) was studied in rats (doses, 20, 100 and 500 mg/kg) and rabbits (50 mg/kg) after bolus administration of calcium salt of N-(5-oxynicotinoyl)-L-glutamic acid (Ampasse preparation). The ONG concentration in the blood serum was determined by HPLC assay with fluorimetric detection. The lower limit of accurate detection for ONG was 100 ng/ml. The ONG pharmacokinetics in rats was linear at relatively small doses (20-100 mg/kg) but nonlinear at a large dose (500 mg/kg). The ONG concentration decay had a two-phase character in both rats and rabbits, so that the pharmacokinetic profiles were fitted to a biexponential equation of the two-compartment model. Systemic pharmacokinetic parameters determined in rats and rabbits, respectively, were as follows: total clearance, 18 and 15 ml/(min kg); steady state distribution volume, 330 and 880 ml/kg; mean retention time, 0.3 and 1.0 h; half-life, 0.73 and 2.3 h. Using the allometric approach to the interspecies extrapolation of the pharmacokinetic data, the half-life of ONG in humans is predicted to be 4 h.

To reveal possible age-dependent variations in the ceftazidime pharmacokinetics, the drug plasma concentrations were determined by HPLC in 10 children aged 2 to 13 years with peritonitis. The blood specimens were collected 0.25, 0.5, 1, 3, 6 and 8 hours after intravenous bolus administration of ceftazidime (Kefadym, Eli Lilly) in a single dose of 20 mg/kg. The mean values of the model-independent parameters were: total clearance (Cl), 3.3 +/- 0.8 ml/min.kg; steady-state distribution volume, 0.32 +/- 0.06 ml/kg; mean residence time, 1.7 +/- 0.4 hours. The C-coordinate of the gravity center was equal to 26 +/- 7 mg/l. A noticeable age-dependent decrease in Cl was detected by comparing the Cl estimates in our study for the children aged 7.0 +/- 3.0 years with earlier findings in children aged 12 years as well as in adults (18 and 26 years) and elderly patients (77 years): 2.5, 2.2, 2.0 and 1.1 ml/min.kg, respectively. A similar trend was observed for the ceftazidime volume of distribution (Varea). Due to the described reduction in Cl and Varea the age-induced changes in the half-life of ceftazidime were negligible. The age-dependent differences in ceftazidime pharmacokinetics should be taken into account in designing rational dosage regimens for the drug administration.

Dosage individualization based on quantitative relationships between pharmacokinetic parameters and anatomophysiological and/or pathological factors, patient's factors (PFs) is of importance in designing optimal regimens. Unfortunately, the attempts to correlate aminoglycoside pharmacokinetic parameters and PFs often failed perhaps due to insufficient numbers of PFs under investigation. That is why we sought to involve more PFs, especially nontraditional ones, for explaining intersubject variability of the amikacin model-independent parameter in 20 patients with purulent inflammatory processes. Amikacin plasma concentrations in specimens collected 0.5, 1, 2, 4, 5 and 6 hours after the drug administration (500 mg, i.v.) were determined with the FRIA-technique (TDx, Abbott). The mean values of the total clearance (Cl), steady-state volume of distribution (Vss) and the mean residence time (MRT) were 87.5 +/- 18.4 ml/(h.kg), 0.33 +/- 0.07 l/kg and 4.0 +/- 0.6 h, respectively. Stepwise multivariate regression analysis made it possible to establish statistically significant correlations between the Cl and 8 PFs, including age, sodium plasma concentrations, plasma osmolarity, partial pressure of oxygen and carbon dioxide, volumes of transfused plasma and blood and artificial pulmonary ventilation (r = 0.99), as well as between the MRT and 6 PFs, including sex, plasma osmolarity, plasma creatinine concentrations, volumes of transfused plasma and artificial pulmonary ventilation (r = 0.94). Multiple correlations were also found between the area under the drug concentration/time curve and 11 PFs (r = 0.99). The coefficient of the multiple correlation between the Vss and volume of the transfused plasma proved to be much lower (r = 0.67). The multiple regression equation for the Cl prediction provided a reliable indirect estimation of the parameter individual values without the amikacin concentration data. Thus, it appeared possible to adjust the aminoglycoside dosage by taking into account 8 PFs before the TDM data were available.

Inactivation of sisomicin in aqueous solutions was studied under various conditions. At pH 4-10 and a temperature of 60 degrees C the inactivation rate constant was equal to (5-10) X 10(-5) hour-1 and remained stable. At lower pH values the inactivation rate constant increased: 5.5 10(-3) (60 degrees C) at pH 0.5. The activation energy of the inactivation reaction was 27 (pH 0.5) and 32 (pH 4.0) kcal/mol. The study on the behaviour of sisomicin in solutions with different pH values under the environmental conditions and in the atmosphere of nitrogen showed that at low pH values the inactivation was mainly determined by hydrolysis of the glycoside bond. Formation of coloured compounds did not include the oxidation reaction. At pH about 7.0 oxidation of the antibiotic or of the products of its degradation with respect to the double bond played a significant role in the inactivation and formation of the coloured substances.