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Pathomorphological and bacteriological changes in albino mice infected with plague and treated with cefotaxime were investigated. The control animals which died within 3 days had structural changes characteristic of generalized plague with lesions in the infection site, regional lymph nodes, spleen, liver and lungs. The plague microbe was isolated from the tissues of all the organs and blood. The animals treated with cefotaxime (200 mg/kg for 7 days) survived. The histological examination conclusively demonstrated the absence of the changes characteristic of generalized plague in their internal organs. The infection process was mainly restricted by the primary complex and was strictly localized. The tissue reaction around the focus in the second part of the experiment developed in accordance with the productive type inflammation followed by the organization and cicatrization. In the bacteriological investigation the plague causative agent was detectable during the first days of the treatment in the site of the infection. During the subsequent days the plague microbe was not detected.

To estimate the in vitro susceptibility of the plague microbe to chemotherapeutics, various experimental models with the maximum closeness to the host conditions were tested. The tests included the assay of the drug antibacterial activity against the plague microbe by the method of two-fold dilutions in biological fluids i.e. human normal (nonimmune) serum (HNS) and guinea pig heparinized blood. Hottinger broth was used as the control. It was shown that any system used for estimation of the drug MIC influenced the plague microbe susceptibility. Thus, the serum complement increased the antibacterial activity of cefotaxime, rifampicin, doxycycline, erythromycin and polymyxin B. In the blood of a susceptible host (guinea pigs) the activity of quinoxydine and dioxydine against the plague microbe markedly increased while the effect of benzylpenicillin, cefotaxime and furazolidone decreased. The data on the in vitro activity of the antibiotics in blood were comparable with those on their in vivo therapeutic efficacy.

Therapeutic efficacies of various drugs were studied comparatively in the treatment of experimental plague in albino mice at the stage of the infection generalization. It was shown that out of the tested drugs such as ciprofloxacin, amikacin, gentamicin, rifampicin and polymyxin B only ciprofloxacin provided a rather high therapeutic effect in the treatment of the plaque septic form. The in vitro and in vivo experiments demonstrated that ciprofloxacin had an antitoxic action on lipopolysaccharide (LPS) and the plague microbe toxin. In comparison to ciprofloxacin, polymyxin B had a higher neutralizing activity. It was found that the efficacy of the experimental plague treatment at the stage of the infection generalization increased with the use of combinations of the drugs with antitoxic and antibacterial activities (ciprofloxacin and polymyxin B).

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.

In a model of experimental plague of albino mice the prophylactic and therapeutic action of ceftazidime by comparison with that of cefotaxime and the combined action of cefotaxime with other antibiotics were studied. The studies showed that the drugs had a high prophylactic and therapeutic action when used in doses of 200 to 400 mg/kg (ceftazidime) and 400 to 800 mg/kg (cefotaxime). The survival of the animals amounted to 80-100 per cent. The therapeutic effect was defined by the drug dose and the treatment term. When the treatment term was decreased to 3 days, ceftazidime proved to be more advantageous than cefotaxime. When the antibiotic dose was insufficient, the treatment efficacy was shown to depend on the infective dose. The use of cefotaxime in combination with aminoglycosides (gentamicin or sisomicin), rifampicin or doxycycline significantly increased the percentage of the animal survival in comparison to the use of the drugs alone and promoted a rapid elimination of the pathogens in the animals. The combined use of cefotaxime and gentamicin or sisomicin as well as cefotaxime and rifampicin had a synergistic action.

The activity of doxycycline and tetracycline against natural strains of the plague microbe of different origin was studied in vitro. The MICs of doxycycline and tetracycline for the majority of the strains were 0.8 and 3.2 micrograms/ml respectively. The efficacy of doxycycline and tetracycline in the prophylaxis and treatment of experimental plague infection was studied comparatively on albino mice. Doxycycline proved to be superior to tetracycline. By using short-term schemes of the treatment and longer intervals between the drug administrations it was shown that doxycycline had a prolonged action. Moreover, the injectable doxycycline was found to be superior to the oral one. The high efficacy of doxycycline in the treatment of the albino mice with experimental plague infection was confirmed by the pathohistological findings. The pathomorphological changes in the animals were limited by local affections in the site of the contamination and the regional lymph nodes followed by the development of infiltration foci.

The therapeutic effect of azlocillin and its combinations with other antibiotics was studied in a model of experimental plague of albino mice. Azlocillin was shown to be efficient in the prophylaxis and treatment of the experimental plague infection. The optimal doses of azlocillin were determined. The protective action of the drug depended on the dose and the time of its administration. The therapeutic effect was mainly defined by the antibiotic dose. The use of azlocillin in not sufficiently active doses in combination with aminoglycosides (gentamicin, sisomicin and amikacin), rifampicin or doxycycline significantly increased the percentage of the animal survival by comparison with that after the use of every antibiotic alone. A synergistic effect was observed when azlocillin was used in combination with rifampicin or amikacin.

Comparative study of the properties of initial capsular (cap+) and non-capsular (cap-) F. tularensis strains has revealed that the non-capsular variants have their specific biological features. The characteristic features of these variants are avirulence and inability to produce an immunogenic effect in sensitive laboratory animals. Cap- mutants, depending on the method of their obtaining, may exhibit different sensitivity to some antibacterial preparations. In contrast to the initial virulent strains, cap- variants are intensively phagocytosed by peritoneal macrophages of white mice and capable of multiplication and survival in these macrophages. F. tularensis non-capsular forms are characterized by higher superoxide-dismutase and neuraminidase activity than the initial strains, which may be the explanation of the phenomenon of their intracellular survival. At the same time the main biochemical signs of cap- strains (citrullinureidase, phosphatase and penicillinidase) remain unchanged, which determines the possibility of their classification with this subspecies.

New methods (selection in medium T with 20% Tween-80, inducing mutations leading to the appearance of resistance to triphenyl tetrazolium chloride or indoxyl phosphate) helped create a collection of F. tularensis stable non-capsular variants from strains of different subspecies. The characteristic features of all F. tularensis cap- variants include inability to serologic tests with erythrocytic diagnosticum, the absence of capsular antigens, sensitivity to normal human serum.

It was shown that the presence of subinhibitory concentrations of ampicillin, cefotaxime or gentamicin in the cultivation medium had a marked inhibitory effect on the catalase activity of plague microbe. The effect depended on the characteristic features of plague microbe strains and the incubation temperature. When the cells of a virulent strain of the plague microbe Y. pestis 1300 were cultivated at a temperature of 37 degrees C on a medium containing the subinhibitory concentrations of ampicillin or cefotaxime, the pathogen virulence for albino mice significantly decreased.

The effect of antibiotics such as amikacin, rifampicin, doxycycline, polymyxin B and cefotaxime on the toxins of the plague microbe (lipopolysaccharide + fraction II according to Beiker) was studied in vitro and in vivo. The study on the antibiotic neutralization of plague toxins revealed that only polymyxin had toxin neutralizing capacity which depended on the dose. Investigation of the polymyxin effect at various stages of plague infection showed that when polymyxin in a dose of 1250 units and a mixture of plague toxins in lethal doses were administered simultaneously to albino mice, the positive effect amounted to 100 per cent. When the antibiotic was administered 30 or 60 minutes later, the antibiotic efficacy proved to be lower by 90 or 76.6 per cent, respectively. The intoxication in later periods (in 90-120 minutes) resulted in a decrease in animal survival up to 40-15 per cent. It was demonstrated on the model of the plague infection in albino mice that the use of amikacin, cefotaxime, rifampicin or doxycycline during polymyxin therapy at the stage of marked generalization of the infection provided a significant increase in the animal survival (60 to 80 per cent) as compared to that after the use of the same drugs alone (0 to 20 per cent).