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Aim: To analyze clinical, bactericidal effectiveness and pharmacokinetics of wide-spectrum antibiotic netromycin (NM)., Materials and Methods: The trial entered 29 patients: 21 with bronchopulmonary diseases (pneumonia and chronic bronchitis), 5 with exacerbation of chronic pyelonephritis, 2 with infectious endocarditis and 1 with peritonsillar abscess., Results: Microbiologically, most of the agents (80.36%) showed sensitivity to NM. Pharmacologically, NM persisted long in blood serum and sputum irrespective of the administration mode. Positive clinical dynamics after NM treatment was achieved in all the patients but one who had a peritonsillar abscess., Conclusion: NM is highly active against both gram-positive and gram-negative flora. Side effects are minimal.

The therapeutic effects of parenteral and oral rifampicins were studied comparatively in a model of experimental plague of albino mice infected subcutaneously and by aerosol. The study showed that in a dose of 25 mg/kg rifampicin was highly efficient in the treatment of the albino mice with experimental glandular plague when the drug was administered either parenterally or orally for 7 days (100-percent survival). The parenteral rifampicin was advantageous when used in lower doses (6.25-12.5 mg/kg) or for a shorter period (3-5 days): 70-100-percent survival against not more than 30 per cent with the oral administration of the drug. It was especially evident when the animals were infected by aerosol. The results made it possible to recommend rifampicin injections in the treatment of the most severe forms of pneumonic plague.

Multifactorial analysis was applied to the study of the combined effect of doxycycline and a polysaccharide of microbial origin in experimental plague infection. A marked synergistic action of the antibiotic and polysaccharide used in subtherapeutic doses in treatment of the infection was observed. By the results of the experiments polynomial statistic models of the 2nd order were designed and nomographs or equal level lines were plotted. The models and nomographs described the animal survival rate and lifespan within a wide range of the control parameters. The dose/time regimens for the use of the polysaccharide combination with doxycycline were optimized on the basis of the multifactorial analysis.

The combined effect of doxycycline and microbial peptidoglycan was studied with multifactorial analysis. The drugs were used preventively and therapeutically. The preventive use of doxycycline in the subtherapeutic doses in combination with the immunomodulator resulted in a significant increase in the survival rate rather than the average life-span (ALS) of the experimental animals. The therapeutic use of the drugs was more efficient than the preventive one and resulted in higher survival and ALS. By the results of the experiments polynomial statistic models of the second order were developed and the equal level curves characterizing the survival rate and ALS were plotted. The dose-time regimens of the combined use of doxycycline an peptidoglycan were optimized.

Comparative efficacy of the use of injection and oral dosage forms of rifampicin in the subtherapeutic doses in combination with peptidoglycan , an immunomodulator of microbial origin, was studied in respect to experimental anthracic infection with application of multifactorial analysis. It was shown that the antibiotic and immunomodulator had a pronounced synergistic effect. Polynomial statistic models were developed and nomograms or equal level curves defining the survival rate and average life-span (ALS) of the experimental animals within a wide range of the antibiotic and immunomodulator doses and the peptidoglycan dosing time were plotted. The combined use of the injection rifampicin in the subtherapeutic doses and the immunomodulator provided a significant increase in the survival rate and ALS, whereas the use of the oral antibiotic in combination with the immunomodulator increased only the ALS and not the survival rate. Multifactorial analysis proved to be an optimal methodical approach to comparative study of various antibiotic dosage forms used in combination with immunomodulators under experimental conditions.

The combined effect of doxycycline and a low molecular weight immunomodulator of microbial origin was studied in experimental plague infection with mathematical design of the experiment. Synergism of the action of the antibiotic and immunomodulator used in subtherapeutic doses was observed. The action was the most pronounced when the drugs were applied therapeutically. On the basis of the multifactorial analysis the regimens for the use of the antibiotic and immunomodulator were optimized.

Multifactorial analysis was applied to the study of the combined effect of rifampicin and a microbial polysaccharide in experimental plague infection. The effect of the antibiotic and immunomodulator was shown to be synergistic. On the basis of the study results polynomial statistic models of the second order were designed and nomograms or equal level lines were plotted which provided optimization of the combined chemo- and immunotherapy.

The combined effect of rifampicin and a microbial peptidoglycan was studied in multifactorial experiments on noninbred mice with plague infection. The effect of rifampicin and the immunomodulator was shown to be synergistic. The results of the multifactorial experiments provided designing of polynomial statistic models of the second order characterizing the animal survival rate and mean life-span and plotting of nomograms or equal level lines useful in optimization of the combined therapy parameters.

Chemotherapeutic efficacy of combined therapy of experimental anthrax infection with subtherapeutic doses of doxycycline and a low molecular weight immunomodulator of microbial origin was studied with mathematical design of the experiment and multifactorial analysis. A marked synergistic effect of oral doxycycline and the immunomodulator was observed. The results of the multifactorial experiment were computer processed and polynomial statistic models (the second order equations) describing the survival rate and mean lifespan (MLS) were derived. The equal level lines characterizing the survival rate and MLS were plotted against the fixed values of the time factor of administering the immunomodulator and the dose of the antibiotic. The doses of the immunomodulator and the time of its administration were optimized with respect to the maximum therapeutic effect with doxycycline subtherapeutic doses.

Comparative chemotherapeutic efficacy of doxycycline administered orally or parenterally was studied on a model of experimental Q fever in guinea pigs and albino mice. The advantage of the parenteral use of the antibiotic was observed only in the treatment of the albino mice. Optimization of the doses and time of doxycycline use providing the maximum therapeutic effect and the required levels of the complement binding antibodies was achieved with employing the multifactorial analysis.

Multifactorial analysis of the combined use of rifampicin and an immunomodulator of the microbial origin, such as peptidoglycan, was performed on a model of experimental Q fever in albino mice. On the basis of the experimental results, statistic polynomial models describing the weight of the murine spleens and the titers of the complement-binding antibodies were designed. It was shown that the action of the immunomodulator and antibiotic was highly synergistic with respect to the chemotherapeutic activity and antibody titers. The preventive use of the immunomodulator yielded a 30-fold decrease in a rifampicin therapeutic dose. The use of the immunomodulator also provided a pronounced immunomodulating effect with respect to humoral immunity. Nomographs for optimizing the dose-time parameters of the antibacterial and immunomodulating therapy were plotted.

Multifactorial analysis of the combined effect of rifampicin and a low molecular immunomodulator of microbial origin in experimental plague infection was performed. Synergism of the antibiotic used in the subtherapeutic doses and the immunomodulator was shown. By the results of the study polynomial statistic models of the second order describing the survival rate and average life-span of the experimental animals were developed and nomographs (equal level curves) were plotted for rapid estimating the therapy quantitative parameters. Optimization of the combined use of rifampicin and the immunomodulator on the basis of the multifactorial analysis was achieved.

The pharmacokinetics of sisomicin was studied on Wistar rats. The antibiotic was used in single or repeated doses of 12.5 and 25 mg/kg. The kinetic data of the antibiotic titration in blood serum within 1 and 24 hours of intramuscular administration of the drug were formalized with the use of a linear two-compartment model. The average values of the elimination constant and the constants of sisomycin transfer from the central compartment into the peripheral one were 0.64, 0.34 and 0.13 hours-1 respectively. The value of the apparent distribution volume in the central compartment was 0.38 ml/kg and that of the stationary and kinetic distribution volumes was 1.37 and 3.06 1/kg respectively. The value of the general clearance was 0.24 1/(kg.hour) and that of the sisomicin half-life was 8.7 hours. Comparison of the antibiotic levels estimated with a model and actually measured in the blood after repeated administrations revealed the drug cumulation. When the antibiotic was used in a dose of 25 mg/kg daily, its cumulation was observed earlier (by the 5th--8th day) than on its use in a dose of 12.5 mg/kg (by the 30th day). Irrespective of the dose, sisomicin cumulation was accompanied by prolongation of the antibiotic half-life in the rats.

The reumycin pharmacokinetics was studied with HPLC on Wistar rats after intravenous injection of the antibiotic in single doses of 2.5, 5 and 10 mg/kg and after its oral administration in single doses of 5 and 10 mg/kg. It was shown that the reumycin pharmacokinetics within the above dose ranges was nonlinear and within every dose could be described by a two-compartmental model. Its nonlinear nature might be associated with saturated binding of the antibiotic by the blood serum proteins. The absolute extent of the reumycin bioavailability after oral administration was 50 per cent. The variability of the reumycin cumulative renal excretion was due to bimodality of distribution of the parameter in the animals. Renal excretion of the intact antibiotic decreased from 35 to 20 per cent with increasing of the dose. The value of the reumycin half-life in humans was predicted (41-46 hours) with the pharmacokinetic animal scale-up.

Sodium fusidin prepared at the All-Union Research Institute of Antibiotics was studied experimentally and clinically. High antibacterial activity of fusidin especially against methicillin-resistant staphylococci was found. The clinical trials showed high efficacy of fusidin in treatment of perichondritis, osteomyelitis, pyodermia, pseudofurunculosis, multiple abscesses of the skin because of its satisfactory penetration into the skin and cartilage tissues, skin and subcutaneous cellular tissue. The tolerance of the drug by most of the patients was satisfactory.

Applicability of the "pharmacokinetic time" concept in animal scale-up was evaluated by the findings of the pharmacokinetic study of doxycycline after its bolus intravenous administration to rats in doses of 9 and 18 mg/kg and to cats as 1-hour constant rate infusion in doses of 3.8 and 7.6 mg/kg. Analysis of the pharmacokinetic profiles in the plot of the logarithmic ratio of concentration/dose to "pharmacokinetic time" i. e. time related to body weight raised to the power 0.25 showed that the slopes of the curves for rats, cats and humans (the literature data, intravenous bolus administration in a dose of 2.9 mg/kg) were practically similar. However, no complete coincidence of the curves was observed. When expressed in the "pharmacokinetic time" scale the half lives were equal to 4.6-5.4, 3.5-3.7 and 5.2 h.kg-0.25 respectively. The difference was 1.5-fold while with using the chronological time the difference was about 5-fold (3.1 hours in rats and 15.1 hours in humans). Therefore, with using the "pharmacokinetic time" 10-fold species differences in the total clearance (0.55 and 0.056 l.h-1.kg-1 in rats and humans respectively) transformed into 2-fold differences (0.37 and 0.16 l.h-1.kg-0.75 respectively). Prediction of doxycycline half lives in humans by the experimental findings was successful.

Differences in the protein-composition of methicillin resistant (MR) and methicillin sensitive (MS) staphylococci were shown by means of disk electrophoresis. Extracellular proteins of MR and MS staphylococci were studied electrophoretically. The study revealed no relation between the culture grouping by the protein spectra and resistance to methicillin. Comparison of the spectra of soluble intracellular proteins showed a certain correlation with methicillin resistance.

The structure of the causative agents isolated from patients with pyoinflammatory infections in 1980-1983 was analysed. It was shown that the surgical and urological infections were mainly caused by gram-negative bacteria. The other pyoinflammatory infections were mainly due to gram-positive cocci. A relatively high frequency of the strains of gram-negative bacteria, especially among Pseudomonas spp. and Enterobacter spp., resistant to aminoglycoside antibiotics, such as gentamicin, sisomycin and tobramycin with preserved sensitivity to amikacin and netilmicin in the majority of the strains was shown. Among the beta-lactam antibiotics cephotaxim and cephalotin were most active against gram-negative bacteria and staphylococci, respectively. The majority of the antibiotic resistant strains of gram-negative bacteria had analogous structures and levels of resistance to 7-12 antibiotics which might indicate the occurrence of 1-2 resistance plasmids among the clinical strains.

Stimulating effect of cyclosporine on growth and invasiveness of tumor xenographts was studied on a model of rat solid sarcoma M-1 transplanted under the kidney capsule in mice. Cyclosporine was administered subcutaneously in a dose of 25 or 75 mg/kg on days 1-7. The stimulating effect of cyclosporine was directly associated with the immunodepressant dose and accompanied by a decrease in the thymus weight. With using cyclosporine the model of xenographts under the kidney capsule can be of value in screening cytostatics and immunomodulators.

The main types of side reactions due to antibiotic therapy are described. The antibiotic groups most often being the cause of side reactions are presented. Dependence of the toxic (organotropic) effect of antibiotics on the therapy scheme, age and pathological changes in the mechanism of their excretion is indicated. The biochemical mechanisms of the side and selective effects of antibiotics are discussed.

Blood pharmacokinetics of the antitumor antibiotic aclarubicin and its metabolites was studied in rats with high performance liquid chromatography. The drug was administered intravenously in single doses of 5 and 10 mg/kg and orally in a single dose of 10 mg/kg. Aclarubicin pharmacokinetics was shown to be nonlinear. However, within every dose level it obeyed a two-compartment model. The nonlinearity could be due to saturation of aclarubicin binding to blood plasma proteins. The blood concentrations of metabolites MA144 N1 and MA144 T1 were close and after 12-18 hours exceeded those of unchanged aclarubicin. The half-lives of aclarubicin and its metabolites ranged from 16 to 21 hours. The MA144 T1 content was not significant. Following oral administration aclarubicin was rapidly absorbed and its bioavailability amounted to 35 per cent. Total bioavailability of aclarubicin, MA144 N1 and MA144 T1 was equal to 89 per cent. This enabled to consider the oral route of aclarubicin administration promising in tumor therapy.

To investigate the evolutionary relationships between the aph(3') genes from different plasmids, the nucleotide sequence of the aph(3') gene from the E. coli R plasmid was determined and compared with the known aph(3') genes of Tn903 and Tn4352. Three point mutations in the structural part of the cloned aph(3') gene caused amino acid changes in the enzyme molecule at positions 19, 27 and 48 beginning from the start codon. The structural part of the gene was followed by two stop codons and a long DNA region containing no nucleotide sequences homologous to the sequences of Tn903 or Tn4352. Both the cloned aph(3') gene and Tn4352 were limited on the left by the spacer sequence and the insertion sequence IS176. Twenty one base pairs deletion abolished the -35 sequence of the promoter suggested for the aph(3') gene of Tn4352 and resulted in formation of a fusion promoter utilizing the -35 box of IS176 and the -10 box of the aph(3') gene. The distance between the -35 and -10 sequences changed from 18 to 17 bp. Changes in the cloned aph(3') gene and the flanking DNA regions resulted in formation of a new promoter and loss of the right IS176 element.

The efficacy of the combinations of aminoglycosides and penicillin with respect to Pseudomonas, Klebsiella and Escherichia strains was estimated with the methods of two-fold serial dilutions of aminoglycosides and constant concentrations of penicillin and the "chess board" method. Correlation between the synergistic effect and sensitivity of the strains to separate components of the combinations was observed. For prediction of the combination efficacy these methods are not useful, since they are labour-intensive and their results are very variable. In this connection a simple informative test is recommended. With the use of this test it is possible to judge the chemotherapeutic efficacy of antibiotics and their combinations by the value of the serum antibacterial activity (titer) against the infection causative agent. The blood serum titer of at least 1:8 is accompanied by a pronounced effect. The test also indirectly provides information on the sensitivity of isolated pathogens and adequacy of the drug blood levels after administration of the chosen dose.

The electrophoretic analysis of the plasmid DNA of multiresistant clinical E. coli strains revealed the presence of extrachromosomal DNA in 97% of the strains. The plasmid nature of resistance was established in 88-100% of E. coli strains resistant to chloramphenicol, ampicillin, streptomycin or kanamycin and in 67% of the strains resistant to tetracyclin. 24 out of 40 strains contained conjugative R-plasmids in which the determinants of resistance to kanamycin, ampicillin and chloramphenicol were transferred most frequently (82-93%), while the determinants of resistance to tetracyclin and streptomycin were transferred less frequently (45% and 35%, respectively). Nonconjugative R-plasmids were detected in 15 out of 40 antibiotic-resistant strains; in these plasmids the determinants of resistance to streptomycin (65%) and tetracyclin (22%) were transferred most frequently.