[Pathomorphological changes in albino mice infected with plague and treated with cefotaxime]. / Patomorfologicheskie izmeneniia v organizme belykh myshei, zarazhennykh chumoi i lechennykh tsefotaximom.

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.

[Increased effectiveness of etiotropic therapy of experimental plague in albino mice at the stage of generalized infection]. / Povyshenie éffectivnosti étiotropnoi terapii éksperimental'noi chymy belykh myshei na stadii generalizatsii infektsii.

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).

[Enhancement of treatment efficacy in experimental plague by the sequential administration of antibiotics]. / Povyshenie éffektivnosti lecheniia éksperimental'noi chumy putem posledovatel'nogo vvedeniia antibiotikov.

It was shown that the use of ampicillin, azlocillin or polymyxin 24 or 96 hours after the plague infection at the background of the every-day use of rifampicin in the doses protecting only 30 per cent of the animals from death provided 80-100-percent survival of the animals. With the every-day use of ampicillin, azlocillin or polymyxin in succession with rifampicin there was observed a 3-fold increases in the survival of the albino mice as compared to those exposed to an analogous dose of rifampicin alone. A decrease in the number of administrations of the above drugs and an increase in the intervals between the administration also resulted in a significant rise of the animal survival in comparison with that after the every-day use of a similar dose of rifampicin.

[Comparative effectiveness of rifampicin for parenteral administration and internal dose in the treatment of experimental plague in albino mice]. / Sravnitel'naia éffektivnost' rifampitsina dlia parenteral'nogo vvedeniia i priema vnutr' pri lechenii éksperimental'noi chumy belykh myshei.

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.

[Prophylactic and therapeutic action of ceftazidime in comparison to that of cefotaxime and combined use of cefotaxime with other antibiotics in experimental plague of albino mice]. / Profilakticheskoe i lechebnoe deistvie tseftazidima v sravnenii s tsefotaksimom i sochetannoe ispol'zovanie tsefotaksima s drugimi antibiotikami pri éksperimental'noi chume belykh myshei.

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.

[A method of sequential administration of antibiotics in preventive treatment of experimental plague in albino mice]. / Metod posledovatel'nogo vvedeniia antibiotikov v predupreditel'nom lechenii éksperimental'noi chumy belykh myshei.

Combination of a betalactam antibiotic (ampicillin or azlocillin) or polymyxin B with rifampicin were studied with their administration in succession at various intervals in an experimental model of plague infection of albino mice. It was shown that when the administration of the betalactams or polymyxin B preceded the administration of rifampicin, the efficacy of the preventive therapy considerably increased. The time of the intervals was noted to be of importance and should be predetermined for every subsequent administration.

[Comparative study of the effect of antibiotics on the vital activity of plague microbe absorbed by macrophages]. / Sravnitel'noe izuchenie vliianiia antibiotikov na zhiznedeiatel'nost' chumnogo mikroba, pogloshchennogo makrofagami.

The influence of aminoglycosides (gentamicin, sisomicin and amikacin), cephalosporins (cefotaxime, ceftazidime and cefazolin) and semisynthetic penicillins (ampicillin and azlocillin) on the vital activity of macrophage-absorbed plague microbe was studied in a model of peritoneal macrophages of albino mice. It was shown that the aminoglycosides and betalactams added to the medium for the cultivation of the macrophages with the absorbed cells of the plaque microbe lowered the intensity of the plague microbe multiplication and promoted the phagocytosis completion when exposed for a prolonged time (24 hours). When the influence was body-mediated (albino mice), even a single administration of the antibiotics was sufficient to retard the vital activity of the macrophage-absorbed plague microbe during the first 6 hours of the observation period. It was also shown that the aminoglycosides were more active than the betalactams.

[Effectiveness of doxycycline in experimental plague]. / Effektivnost' doksitsiklina pri éksperimental'noi chume.

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.

[Efficacy of rifampicin in experimental plague infection]. / Effektivnost' rifampitsina pri éksperimental'noi chumnoi infektsii.

The effect of rifampicin on the plague microbe was studied in vitro and in albino mice with experimental plague infection. The rifampicin MIC with respect to 50 strains of the plague microbe of different origin in the tests on the Hottinger agar ranged from 1.6 to 6.4 micrograms/ml. High efficacy of rifampicin was shown in the prophylaxis and treatment of experimental plague when used in doses of 25 and 50 mg/kg once every 24 hours for 5 to 7 days. Rifampicin prevented the development of plague in at least 80 per cent of the albino mice when it was administered 1, 3, 6 and 24 hours prior to the infection. The antibiotic had a prolonged action and preserved its high efficacy after the administration at intervals of 48 and 72 hours.

[Therapeutic effect of azlocillin and its combinations with other antibiotics in experimental plague infection]. / Lechebnoe deistvie azlotsillina i ego sochetanii s drugimi antibiotikami pri éksperimental'noi chume.

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.

[Effectiveness of the new quinolones, ciprofloxacin and pefloxacin in experimental plague]. / Izuchenie éffektivenosti novykh khinolonov--tsiprofloksatsina i pefloksatsina pri éksperimental'noi chume.

Efficacy of ciprofloxacin and pefloxacin in plague infection was studies on albino mice by comparison with that of nalidixic acid. The mice were contaminated subcutaneously. The treatment with the drugs was started 6 or 24 hours after the contamination. The MICs of ciprofloxacin, pefloxacin and nalidixic acid were 0.01 to 0.02, 0.15 and 1.25 to 2.5 micrograms/ml respectively. By the ED50 ciprofloxacin proved to be the most efficient. Pefloxacin was 6 times less efficient and nalidixic acid was 100 times less efficient. The quinolones were shown to be highly efficient when administered at 48-hour intervals.

[Effectiveness of cefotaxime in experimental plague infection]. / Effektivnost' tsefotaksima pri eksperimental'noi chumnoi infektsii.

Cefotaxime was shown highly efficient in prophylaxis and treatment of experimental plague infection in albino mice. The in vitro activity of cefotaxime against natural strains of the plague microbe was 32 to 64 times higher than that of cefazolin, cephalothin and cefmetazole. The combined use of cefotaxime with amikacin significantly increased the percentage of the survived albino mice with plague infection as compared to the use of the antibiotics alone.

[Effectiveness of phosphomycin and its combinations with amikacin and cefotaxime in experimental plague infection]. / Izuchenie éffektivnost' fosfomitsina i ego sochetanii s amikatsinom i tsefotaksimom pri éksperimental'noi chumnoi infektsii.

When administered intramuscularly in doses of 8 and 16 mg/mouse, phosphomycin was highly active in the treatment of albino mice with experimental plague infection (80-100-percent protection of the animals from death). Combinations of phosphomycin with cefotaxime in inefficient or not sufficiently efficient doses had a synergistic effect. When the albino mice were treated with combinations of phosphomycin and amikacin, the percentage of the survived animals significantly increased in comparison to that after the use of the antibiotics alone.

[Detoxifying effect of antibiotics and their effectiveness in experimental plague at the stage of explicit intoxication]. / Detoksitsiruiushchee deistvie antibiotikov i ikh éffektivnost' pri éksperimental'noi chume na stadii vyrazhennoi intoksikatsii.

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).

[Antibiotics of the aminoglycoside group (gentamicin, sisomicin and amikacin) in the prevention and treatment of experimental plague]. / Antibiotiki gruppy aminoglikozidov (gentamitsin, sizomitsin, amikatsin) v profilaktike i lechenii éksperimental'noi chumnoi infektsii.

Activity of aminoglycosides such as gentamicin, sisomicin and amikacin against plague microbe strains of natural origin was studied in vitro. It was also studied in prophylaxis and treatment of experimental plague infection in albino mice. The MAC of gentamicin and sisomicin for 50 strains of the plague microbe was 0.2-1.6 micrograms/ml. For the majority of the strains it was 0.4 micrograms/ml. The amikacin MICs were 0.4-3.2 and 0.8 micrograms/ml, respectively. High efficacy of gentamicin, sisomicin and amikacin was shown in prophylaxis and treatment of experimental plague infection in albino mice. The optimal doses of the antibiotics were determined. Under definite conditions such as the use of short-term regimens and higher intervals, advantages of sisomicin over gentamicin and amikacin in prophylaxis of experimental plague infection were observed.

[Multifactorial analysis of combined use of an antibiotic and peptidoglycan of microbial origin in experimental plague]. / Mnogofaktornyi analiz kombinirovannogo primeneniia antibiotika i peptidoglikana mikrobnogo proiskhozhdeniia pri éksperimental'noi chumnoi infektsii.

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.

[Multifactor study of combined effects of an antibiotic and polysaccharide in experimental infection]. / Izuchenie v mnogofaktornom éksperimente sochetannogo deistviia antibiotika i polisakharida pri éksperimental'noinfektsii.

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.

[Chromosomal resistance of plague agent to quinolones]. / Khromosomnaia ustoichivost' chumnogo mikroba k khinolonam.

The nature of increasing chromosomal resistance to quinolones was studied in a model of the plague microbe. Five virulent strains of the natural plague microbe (Y. pestis) were used in the experiment: 363 (1/1479), 231, 2385, 2442 and 2444. The one-stage procedure for isolation of the mutants was applied. It was shown that the frequency of the one-stage mutants resistant to oxalinic acid, pefloxacin and ciprofloxacin amounted to 10(-9)-10(-11) and was 2 to 3 orders of magnitude lower than that of the mutants resistant to nalidixic acid. Two types of the plague microbe mutants resistant to the quinolones were detected: those resistant to the quinolones to the generations (Nalr-phenotype) and those resistant to the representatives of the 3rd generation quinolones (Nals-phenotype). The quinolones were not efficient in the treatment of albino mice with experimental plague caused by the quinolone-resistant forms of the plague microbe.

[A multifactorial analysis of the combined action of an antibiotic and a low-molecular immunomodulator of microbial origin in experimental plague infection]. / Mnogofaktornyi analiz sochetannogo deistviia antibiotika i nizkomolekuliarnogo immunomoduliatora mikrobnogo proiskhozhdeniia pri éksperimental'noi chumnoi infektsii.

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.