Effect of antibiotics on indices of immunologic reactivity in mice

The effect of ristomycin, chloramphenicol, kanamycin, benzylpenicillin, streptomycin, and cephaloridine on the indices of cellular and humoral immunity was studied comparatively on intact animals and on animals with secondary immune deficiency. The study of the antibiotic effect on the count of rosette-forming lymphocytes (RFL) and the total count of lymphocytes showed that all the antibiotics except streptomycin induced a significant decrease in the count of RFL. The most active was kanamycin. It lowered the count of RFL 5-fold as compared to the control. The total count of lymphocytes was lowered after administration of ristomycin, chloramphenicol and kanamycin. In the animals with immune deficiency induced by cyclophosphamide benzylpenicillin potentiated the inhibitory effect of cyclophosphamide on the weight of the lymphoid organs, while streptomycin lowered the effect of cyclophosphamide. No such effect was observed with the use of the other antibiotics. The data indicated the necessity of taking into account the effect of various antibiotics on the immune system, especially under conditions of immune deficiency.     

Eremomycin--a new antibiotic of the polycyclic glycopeptide group

Eremomycin is a novel antibacterial antibiotic. It was isolated at the Institute of New Antibiotics, the USSR Academy of Medical Sciences from the culture fluid of actinomycete INA-238. By its physico-chemical and biological properties the antibiotic was classified as belonging to the group of polycyclic glycopeptides. Chemical structure of eremomycin was asserted and it was shown to be a new representative of the group close by its structure to vancomycin and differing from it by the carbohydrate composition and structure of tri-phenoxytriaminotricarboxylic acid. By its anti-bacterial spectrum eremomycin was found to be close to ristomycin and vancomycin. Still, its activity was 2-10 times higher. The antibiotic was several times less toxic than vancomycin. Unlike vancomycin and ristomycin, the novel antibiotic induced no tissue necrosis after its intramuscular administration. The chemotherapeutic indices of eremomycin in treatment of staphylococcal and streptococcal sepsis in albino mice exceeded 10 times those of vancomycin. At present eremomycin is under clinical trials.     

Preclinical toxicological study of the new antibiotic eremomycin. Chronic toxicity and effect on intrauterine development of rats

Toxicity of eremomycin was studied after its multiple parenteral administration to albino rats, guinea pigs and dogs in doses equivalent by the body surface to the daily doses for humans i. e. 1 and 3 g. The antibiotic was administered for 1 to 6 months. Tolerance of the antibiotic by the dogs after intravenous and intramuscular administration was satisfactory. In some animals there were observed an insignificant increase in the activity of alanine aminotransferase and a rise in the level of urea in blood serum. Pathomorphological examination of the internal organs of the albino rats and dogs showed that in high doses the antibiotic could have a damaging effect on the kidneys and epithelium of the gastrointestinal tract. The level of the damages depended on the dose of the antibiotic and duration of its use. The damages induced by eremomycin were reversible. It had no marked effect on the peripheral blood count, coagulation system and erythrocyte resistance. In the tested doses the antibiotic had no unfavourable effect on the hearing function in the experiments with guinea pigs. Studies with rats revealed that eremomycin had no teratogenic effect. A slightly pronounced embryotoxic action was observed only after using the antibiotic in doses exceeding more than 12 times the approximate therapeutic dose.     

Experimental study of the antibacterial activity and chemotherapeutic efficacy of the novel glycopeptide eremomycin

The study of antibacterial and chemotherapeutic activity of eremomycin, a novel glycopeptide antibiotic showed that it inhibited the growth of gram positive and acid fast microbes. The antibacterial spectrum of the novel glycopeptide was close to that of ristomycin and vancomycin. However, the in vitro antibacterial activity of eremomycin was 2-10 times higher than that of ristomycin and vancomycin. It also inhibited the growth of oxacillin resistant microbes at concentrations 5.20 times lower than those of vancomycin and ristomycin. By the therapeutic efficacy in albino mice with staphylococcal or streptococcal sepsis eremomycin was 2-4 times as superior as vancomycin and ristomycin and by the chemotherapeutic indices it was more than 10 times as superior.     

In vitro activity of a new glycopeptide antibiotic eremomycin in relation to obligate anaerobic Gram-positive bacteria]

Antibacterial activity of eremomycin, a novel glycopeptide antibiotic, against obligate anaerobic Gram-positive++ bacteria was studied. Eremomycin was shown to inhibit the growth of obligate anaerobic Gram-positive++ cocci and bacteria belonging to Clostridium in rather low concentrations and within narrow ranges of the MIC which was indicative of the antibiotic undoubted advantages. The antibacterial activity of eremomycin was 2 times as high as that of vancomycin and 8 times as high as that of ristomycin with respect to Gram-positive++ anaerobic cocci. Pathogenic strains of Clostridium spp. were 2 to 4 times more sensitive to eremomycin than to vancomycin. A significant property of the novel glycopeptide antibiotic was shown to be its capacity for inhibiting the growth of Gram-positive++ aerobic and obligate anaerobic cocci within the same concentration ranges which might be of importance in monotherapy of mixed aerobic and anaerobic infections.     

Study of the sorption of glycopeptide antibiotics on an ultradisperse carbon sorbent

The sorption capacity of a novel ultradisperse carbon sorbent (UDCS) towards antibiotics of the glycopeptide group, namely, eremomycin, vancomycin, ristomycin A, and teicoplanin A2, has been studied. The conditions for maximum sorption of the antibiotics from solutions have been determined, and a mathematical model of the sorption of the antibiotics of the above named group has been put forward.     

Antibiotic sensitivity of plague microbe strains from foreign countries]

The method of serial dilutions on the Hottinger agar was applied to comparative assay of antibiotic sensitivity in 50 strains of the plague microbe isolated abroad and in 5 strains isolated in the plague focus in the Central Caucasus. The antibiotics used in the assay were the following: streptomycin, gentamicin, doxycycline, monomycin, kanamycin, tetracycline, erythromycin, ristomycin, lincomycin and polymyxin M. Irrespective of the origin, all the isolates were resistant to erythromycin, lincomycin and polymyxin M. The levels of the sensitivity to the other antibiotics were different. The data serve as a ground for the statement that there is no tendency to development of antibiotic resistance in the plague microbe in patients treated with high doses of the antibiotics and mainly streptomycin. Along with streptomycin, such antibiotics as gentamicin, tetracycline, doxycycline and kanamycin are useful in the therapy of plague and require further investigation.     

Fluctuations in antibiotic resistances of gram-negative rods in one hospital, 1961-70, with comment on kanamycin-neomycin relationships

Records of the percentages of various types of gram-negative rods resistant to six antibiotics are presented for the years 1961 to 1969 with additional notes on 1970. Gross amounts of each antibiotic used in each of the years are also depicted. Resistance-factor transference does not seem to be an important factor but levels of antibiotic usage do seem to affect the percentages of resistant strains found. In the case of kanamycin, extensive use of neomycin appears to have produced much cross-resistance. Free use of polymyxins does not seem to increase resistant percentages.     

Eremomycin in the treatment of antibiotic-associated colitis in golden hamsters]

The efficacy of eremomycin, a new glycopeptide antibiotic, was studied on a model of antibiotic-associated colitis in golden hamsters. The colitis was induced by intraperitoneal or intragastric administration of lincomycin. In a dose of 100 mg/kg administered orally once a day for 5 days eremomycin protected the animals from the lincomycin-induced colitis: some animals survived, the others died in later periods. When the animals were infected with a pathogenetic strain of Clostridium difficile followed by exposure to lincomycin the use of eremomycin produced the similar effect.     

Effect of an interferon preparation on increasing bacterial sensitivity to antibiotics

Under the effect of human leukocytic alpha-interferon-II for injections there was observed an increase in sensitivity of bacteria to benzylpenicillin, ristomycin, novobiocin, streptomycin, kanamycin, monomycin and erythromycin. A higher antibacterial effect of the penicillin and erythromycin was recorded only with respect to initially resistant strains of staphylococci. For the antibiotic resistant strains of staphylococci the MICs of the penicillin and erythromycin decreased on the average 17.8 and 208 times (p less than 0.001) respectively. The interferon had no effect on sensitivity of bacteria to chloramphenicol.     

Comparative study of the therapeutic effect of the glycopeptide antibiotics eremomycin, vancomycin and ristomycin in a model of antibiotic-associated colitis in golden hamsters]

Experiments with a model of intraperitoneal or intragastric lincomycin-induced fatal colitis indicated that eremomycin, vancomycin and ristomycin administered orally in daily doses of 100, 100 and 200 mg/kg, respectively, for 5 days protected the animals from development of antibiotic-associated colitis (AAC), which was evident from prolongation of their life-span to 10-23 days against 3-9 days in the controls. Eremomycin administered intraperitoneally according to an analogous scheme protected the animals from development of AAC, prevented 45 per cent of the animals from death and prolonged the life-span of the other animals to 15-28 days against 3-9 days in the controls. Vancomycin administered intraperitoneally was somewhat more efficient. Still, unlike eremomycin it had a local irritating effect. The protective effect of ristomycin administered intraperitoneally was much lower than that of vancomycin and eremomycin.     

Study of the activity of a new glycopeptide antibiotic eremomycin combined with tobramycin against Staphylococci in vitro

Eremomycin is an original natural antibiotic with glycopeptide structure isolated at the Institute of New Antibiotics, the USSR Academy of Medical Sciences. Activity of eremomycin alone or in combination with tobramycin was studied with using 25 clinical strains of staphylococci. 56 and 88 per cent of the strains were respectively resistant to gentamicin and kanamycin, two aminoglycoside antibiotics. All the staphylococcal strains were sensitive to eremomycin in concentrations of 0.12 to 1 microgram/ml. The MIC of tobramycin for 10 (40 per cent) sensitive strains ranged within 0.25-2 micrograms/ml. For 60 per cent of the strains the MIC was equal to or higher than 16 micrograms/ml. When eremomycin was used in combination with tobramycin the antibacterial effect with respect to 17 strains (68 per cent) increased. In 32 per cent of the strains the effect was synergistic and in 36 per cent of the strains it was additive. Indifference and antagonism were detected with respect to 7 (28 per cent) and 1 (4% per cent) strains respectively. No significant difference was shown in manifestation of the synergistic-additive nature of eremomycin and tobramycin interaction with respect to the tobramycin sensitive and resistant strains.     

Ability of vancomycin-group antibiotics to induce or to inhibit thrombocyte agglutination

The effect of 4 vancomycin antibiotics on factor VIII-dependent agglutination of thrombocytes was studied. Significant similarity, both quantitative and qualitative, between ristocetin and ristomycin was found. In this connection ristomycin may be used for determination of the so-called ristocetin cofactor. Actinoidin and vancomycin inhibited agglutination of platelets induced by ristocetin or ristomycin in platelet-enriched plasma with citrate or EDTA the same as in the system contaning platelets treated with formalin and did not inhibit agglutination induced by the bovine factor VIII. The 4 antibiotics induced precipitation of the plasma protein. Vancomycin was most active and actinoidin ws lest active in this respect. Ristocetin and ristomycin also possessed such capacity, the effect of the latter being higher. Actinoidin and vancomycin did not prevent the immediate effect of light absorption increasing due to addition of ristocetin or ristomycin to fixed platelets in concentrations completely inhibiting agglutination of platelets in the presence of the protein cofactor. Inhibition of this direct effect of ristocetin and ristomycin was observd only at higher concentrations, which indicated that this effect was not probably associated with agglutination. The results of the study on various ristomycin derivatives showed that methylated carboxylic groups and free hydroxyls of phenol may play the main role in ristomycin binding with the thrombocytic membrane and/or protein cofactor.     

Experimental study on chemotherapeutic efficacy, acute toxic action and nephrotoxicity of combinations of eremomycin with tobramycin

Chemotherapeutic efficacy of eremomycin in combination with tobramycin was investigated on a model of experimental sepsis of albino mice caused by Staphylococcus aureus cultures resistant to methicillin. Eremomycin is a novel original antibiotic of the glycopeptide structure isolated in the USSR and tobramycin is an aminoglycoside. Acute toxicity of the combination with a wide range of the dose fixed proportions was studied on mice and the nephrotoxic action of the antibiotics and their combinations administered intravenously for 5 days was studied on albino rats. The experiments showed that the chemotherapeutic effect of eremomycin in combination with tobramycin was of synergistic nature. Acute toxicity of the combined drugs mainly summed up and somewhat increased when the proportion of tobramycin and eremomycin was 1:2.4 or 1:3.6. Eremomycin had a dose-depended nephrotoxicity. Summing up of the nephrotoxic action of the drugs on their combined use was observed.     

Sorbents with immobilized glycopeptide antibiotics for separating optical isomers by high-performance liquid chromatography

Chiral sorbents for HPLC separation of optical isomers carrying glycopeptide antibiotics (eremomycin or its eremosaminyl aglycon, ristomycin, or vancomycin) fixed onto the surface of silica gel have been synthesized. The patterns of the retention and separation of profen isomers and their dependence on the nature of the chiral selector and the eluant composition have been studied. The sorbents were shown to be highly enantiospecific in separating the isomers of alpha-amino-, alpha-hydroxy-, and alpha-methylphenylcarboxylic acids (profens).     

Sorbents with immobilized glycopeptide antibiotics for separating optical isomers by high-performance liquid chromatography

Chiral sorbents for HPLC separation of optical isomers carrying glycopeptide antibiotics (eremomycin or its eremosaminyl aglycon, ristomycin, or vancomycin) fixed onto the surface of silica gel have been synthesized. The patterns of the retention and separation of profen isomers and their dependence on the nature of the chiral selector and the eluant composition have been studied. The sorbents were shown to be highly enantiospecific in separating the isomers of α-amino-, α-hydroxy-, and α-methylphenylcarboxylic acids (profens)     

Morphological changes in the digestive organs on the administration of the antineoplastic antibiotics, rubomycin and carminomycin

The effect of antitumour antibiotics, such as rubomycin and karminomycin on the digestive tract as one of the most vulnerable systems during chemotherapy was studied. Investigation of the tongue, oesophagus, stomach, small and large intestine of mice with the current morphological and some histochemical methods showed that the most pronounced changes in the above organs occurred during the first 10 days after the drug administration. The damages were of the same type, i.e. dystrophic changes in the tegmental and granular epithelium with edema and infiltration of the mucosa and tunica submucosa. The drugs induced a decrease in the levels of the nucleic acids, protein and hydrolytic enzymes and impairement of the distribution pattern of these substances in the cells. Karminomycin had a more pronounced effect and its damaging effect was more stable as compared to rubomycin.     

Streptomycin and kanamycin level in the blood and lungs of guinea pigs when the antibiotics are administered by inhalation and intramuscularly]

Streptomycin and kanamycin levels in the blood and lung tissue after the antibiotic inhalation or intramuscular administration were studied comparatively on 86 healthy guinea pigs. The antibiotics were inhaled with the help of the nozzle or ultrasonic aerozol apparatus. The studies showed statistically reliable advantages of the ultrasonic aerosols in attaining high levels of streptomycin and kanamycin preserved for prolonged periods of time in the lungs of the experimental animals as compared to the intramuscular administration route or the aerosols introduced with the help of the pneumatic inhaler. After inhalation of the ultrasonic aerosols the levels of streptomycin in the lung tissue of the guinea pigs were 5 times higher than those after inhalation of the nozzle aerosols and 64 times higher than those after the antibiotic intramuscular administration. As for kanamycin the respective values were 2 and 14 times higher.     

Experimental protective action of kanamycin, ampicillin and their combination with methyluracil and pyrogenal]

Efficacy of kanamycin, ampicillin and their combinations with methyluracyl and pyrogenal in experimental Coli infections was studied. The antibiotics were administered an hour after the infection. Methyluracyl and pyrogenal were used according to 2 schemes. Scheme No. I: the drug is used daily for 7 days in increasing doses, the last dose is administered 24 hours before the infection. Scheme No. 2: the drug is used once at the moment of the infection. The methyluracyl doses were: 0.5, 1.0, 2.5 mg and 5 mg and 5 mg per a mouse during the following 4 days. The pyrrogenal doses were: 5, 10, 15, 25, 30 and 35 minimum pyrogenic doses. 5 mg of methyluracyl and 35 minimum pyrogenic doses of pyrogenal were used according to scheme No. 2. The most pronounced increase in the efficacy of kanamycin, ampicillin and their combination was observed in the animals treated simultaneously with methyluracyl and pyrogenal according to scheme No. 1. The efficacy of kanamycin and ampicillin increased 3 and 2.68 times respectively. ED50 of kanamycin and ampicillin used in combination in the animals treated with methyluracyl and pyrogenal was lowered 4 and 2.9 times respectively as compared to that in the animal groups treated only with the antibiotic combination and 21 and 15.2 times respectively when the antibiotics were used alone. Sanation of the animal organs was also rather successful. A single administration of methyluracyl and pyrogenal simultaneously with the infection (scheme No. 2) had a lower effect on the efficacy.     

Survey of antibiotic prophylaxis in gastrointestinal surgery in Scotland.

The current use of prophylactic antibiotics in gastrointestinal surgery in Scotland was established by postal questionnaire. Twenty-one per cent of surgeons used prophylactic antibiotics during cholecystectomy, 49% during appendicectomy, and 95% for elective colorectal surgery. Two-thirds of those surgeons who did not provide routine antibiotic cover considered that the incidence of wound sepsis in their surgical practice was too low to merit special measures. Most surgeons using prophylaxis chose an appropriate antibiotic. The parenteral route for administration of antibiotic was used by 93% of surgeons during cholecystectomy, 29% during appendicectomy, and 45% in elective colorectal surgery. Most did not prolong cover beyond 24 hours postoperatively. This survey shows that the concepts governing the use of antibiotic prophylaxis have been absorbed into current surgical practice. Most surgeons used appropriate antibiotic regimens; many prefer the parenteral route of administration; most do not prolong cover beyond 24 hours.