Demonstration of non-inferiority of a novel combination intramammary antimicrobial in the treatment of clinical mastitis.

AIM: To test the non-inferiority of a novel combination intramammary product containing penicillin and cloxacillin to a reference intramammary product containing oxytetracycline, oleandomycin, neomycin and prednisolone with regard to bacteriological cure and clinical cure. METHODS: Clinical cases of mastitis were sourced from 30 spring-calving dairy farms in the Southland region of New Zealand. Affected quarters were infused three times at 24 hourly intervals with either the novel combination product containing 1 g penicillin and 200 mg cloxacillin, or a reference product containing 200 mg oxytetracycline, 100 mg oleandomycin, 100 mg neomycin and 5 mg prednisolone. Cows were enrolled when a farmer detected a case of clinical mastitis. Milk samples were collected for microbiological culture immediately before treatment (Day 0) and on Days 9, 16 and 23. Bacteriological cure was compared for 187 and 178 quarters treated with the reference and novel product, respectively, and clinical cure was compared for 235 and 223 quarters, respectively. Non-inferiority was assessed by calculating the difference in cure rates between the two products and constructing a 95% CI around the difference, using the variance inflation factor to account for herd level clustering. The non-inferiority margin was 20% for both bacteriological and clinical cure. Generalising estimating equation models were used to determine predictor variables. RESULTS: The bacteriological cure percentage, adjusted to account for herd-level clustering, was 8.5 (95% CI=-1.7-21.8)% higher for quarters treated with the novel than the reference product. The adjusted clinical cure percentage was 0.3 (95% CI=-11.2-12.0)% higher for clinical quarters treated with the novel than the reference product. Bacterial species was the only covariate for bacteriological cure (p=0.003), and quarter score at enrolment (indicating udder inflammation) was the only covariate for clinical cure (p=0.032) in the multivariable models. CONCLUSION: The novel combination product was demonstrated to be non-inferior to the reference product with regards to both bacteriological cure and clinical cure. CLINICAL RELEVANCE: Clinicians treating mastitis now have access to this novel combination intramammary product, and demonstration of its non-inferiority compared to the existing reference product will provide options for treatment approaches. The novel product contains fewer antimicrobials; which are of a narrower spectrum of activity.

Pharmacokinetics of oleandomycin in dogs after intravenous or oral administration alone and after pretreatment with metamizole or dexamethasone.

The pharmacokinetics of oleandomycin (OLD) after intravenous and oral administration, both alone and after intramuscular pretreatment with metamizole or dexamethasone, were studied in healthy dogs. After intravenous injection of OLD alone (10 mg/kg as bolus), the elimination half-life (t 1/2 beta, volume of distribution (Vd,area), body clearance (ClB) and area under the concentration time curve (AUC) were 1.60 h, 1.11 L/kg. 7.36 (ml/kg)/min and 21.66 microg h/ml, respectively. There were no statistically significant differences following pretreatment with metamizole or dexamethasone. After oral administration of OLD alone, the t 1/2 beta, maximum plasma concentrations (Cmax), time of Cmax (tmax), mean absorption time (MAT) and absolute bioavailability (Fabs) were 1.6 h, 5.34 microg/ml, 1.5 h, 1.34 h and 84.29%, respectively. Pretreatment with metamizole caused a significantly decreased value for Cmax (2.93 microg/ml) but the MAT value (2.23 h) was significantly increased. Statistically significant changes in the pharmacokinetic parameters of OLD following oral administration were also observed as a result of pretreatment with dexamethasone. The Cmax was increased (8.24 microg/ml) and the tmax (0.5 h) and MAT (0.45 h) were lower.

[The dynamic serological reactions after treating patients with early forms of syphilis by the single-course shortened reserve method]. / Dinamika serologicheskikh reaktsii posle lecheniia bol'nykh rannimi formami sifilisa odnokursovym ukorochennym rezervnym metodom.

A total of 156 patients with early syphilis were treated with tetracyclin and oletetrin. The drugs were administered 4 times daily (every 6 hrs) in a dose of 0.5 g (daily dose 2.0 g). Patients with primary seropositive syphilis were treated for 20 days, the dose per course being 40 g, those with secondary fresh syphilis for 25 days, dose per course 50 g, those with secondary recurring syphilis for 40 days, dose per course 80 g. The treatment was well tolerated by all the patients. Early negative results of specific serologic tests after treatment confirm the efficacy of the suggested method.

[The immediate results of treating patients with infectious forms of syphilis by the abbreviated single-course reserve method]. / Blizhaishie rezul'taty lecheniia bol'nykh zaraznymi formami sifilisa ukorochennym odnokursovym rezervnym metodom.

The results of rapid single-course oletetrine and tetracycline therapy of early syphilis are analyzed. The time of Treponema pallidum disappearance from syphilid discharge, of syphilid regression, and of the first negative results of the routine serologic tests, immunofluorescence 200/ABC and T. pallidum immobilization tests, as well as the blood serum tetracycline level indicate a high therapeutic efficacy of this method and recommend it for wide use.

[Tolerance for tetraolean i.m. and the blood levels in agricultural animals]. / Ponosimost na tetraolean i. m. i kruvni niva pri selskostopanski zhivotni.

Studied was a drug formula of tetraolean for i/m application, containing tetracycline hydrochloride and oleandomycin phosphate in a 2:1 ratio, produced by the Antibiotic Works, Razgrad, and released in flasks of 500 mg and 1.0 g. It was followed up with regard to its tolerable serum concentrations for rabbits, calves, pigs, and horses. It was found that in therapeutic amounts tetraolean was well tolerated and did not lead to local and general disturbances. In higher doses it was found to form transient oedema in the site of injection. Intramuscularly, tetraolean was well absorbed in the site of application, and, according to the animal species, it developed proper plasmal therapeutic concentrations at the following rates: calves--20 mg/kg body mass at 12-hour intervals; pigs--10 mg/kg at 6-hr intervals, or 20 mg/kg at 12-hr intervals; horses--10 mg/kg at 12-hr intervals or 20 mg/kg at 24-hr intervals.

[Combined antibiotic therapy following heart surgery]. / Kombinirovannaia antibiotikoterapiia u bol'nykh posle operatsii na serdtse.

In vitro efficacy of combinations of broad and narrow spectrum semi-synthetic penicillins, broad spectrum semi-synthetic penicillins with macrolides or aminoglycosides and tetracyclines with other biosynthetic antibiotics was studied with respect to the causative agents of surgical infections. Correlation between the sensitivity of the isolates and the antibiotics levels in the organism of the surgical patients was shown. The role of the etiological factor in the development of the post-operative complications in the patients after surgical operations on the heart was elucidated. The most rational schemes of the antibiotic use in therapy of the patients with purulent complications after operations on the open heart were developed and the maximum doses of different semi-synthetic penicillins for the treatment of patients with purulent processes after operations under conditions of artificial blood circulation were determined.

[The clinical effect of antibiotics in the macrolide family on bronchial asthma. Non-antimicrobial actions of oleandomycin [author's transl)].

Non-antimicrobial actions of oleandomycin (triacetyloleandomycin and oleandomycin phosphate) were studied in patients with bronchial asthma. Twenty-one cases of the disease without associating infections entered the study, and they were given 750mg of oleandomycin or triacetryloleandomycin in three divided doses daily for two weeks. Clinical manifestations and laboratory findings were compared to assess the effectiveness of the antibiotic therapy between the three 2-week periods before, during and after the therapy. Improvements in clinical manifestations were attained in 11 of 21 cases (52.3%), and last after discontinuance of the therapy in 8(38.1%). The blood level of 11-OHCS as determined by the Demoorr's fluorescence method increased by greater than 20% at the end of thearpy in 7 of 18 cases (38.9%). In 5 of the 7 cases favorable responses were seen clinically to the oleandomycin therapy. The serum IgE level determined by the radioimmunosorbent test was compared before and after the therapy to reveal that oleandomycin caused decrease of IgE in 10 and increase in 9 of 20 cases examined. The oleandomycin therapy resulted increases by greater than 20% of the vital capacity and FEV 1.0 in 2 and 3, respectively, of 15 cases. Jaundice in association with elevations of the GOT, GPT and alkaline phosphatase developed in one patient, and generalized skin eruption in another. Both of these cases were given triacetyloleandomycin.

[Effect of successive cyclic administration of oleandomycin and tetracycline on the immunogenic reactivity and indices of non-specific bodily resistance in experimental staphylococcal sepsis]. / Vliianie posledovatel'nogo tsiklovogo vvedeniia oleandomitsina i tetratsiklina na immunogennuiu reaktivnost' i pokazateli nespetsificheskoi rezistentnosti organizma pri éksperimental'nom stafilokokkovom sepsise.

The effect of subsequent cyclic administration of oleandomycin and tetracycline on the titer of the complement, the content of lysozyme, the bactericidal properties of the serum and the presence of the antibiotic specific antibodies in the blood serum found in the Hoigne reaction were studied on rabbits. It was found that the subsequent cyclic administration of the antibiotics to both the intact animals and the animals with experimental staphylococcal sepsis was accompanied by an increase in the titer of the complement only on the 7th day of administration of oleandomycin, the first antibiotic. The subsequent administration of tetracycline and especially discontinuation of the antibiotics use resulted in a significant, stable and prolonged decrease in the complement titer. The cyclic subsequent administration of oleandomycin and tetracycline for 7 days was accompanied by an increase in the lysozyme content and serum bactericidal properties. Changes in the factors of non-specific resistance under the effect of the subsequent cyclic administration of oleandomycin and tetracycline on both the intact animals and the animals with experimental staphylococcal sepsis were accompanied by an appearance, progressive increase and prolonged preservation in the serum of the antibiotic specific antibodies found in the Hoigne reaction. A possibility of producing specific antibodies simultaneously to the 2 antibiotics, i. e. oleandomycin and tetracycline in their administration in subsequent 7-day cycles was shown.

[Olemorphocycline treatment of calculous and noncalculous pyelonephritis]. / Lechenie olemorfotsiklinom bol'nykh kal'kuleznym i nekal'kuleznym pielonefritom

40 patients suffering from calculous and non-calculous pyelonephrits were treated with olemorphocycline administered intravenously in a dose of 250 00 Units 2 times a day for 5--7 days. The clinical effect was observed in 62.5 per cent of the cases. In 54.7 per cent of the cases the isolates were resistant to oleandomycin and morphocycline. The kidney tissue and urine from the kidney pelvis taken during surgical operations of 20 patients were plated out. Staphylocci were most often detected in the platings of the kidney tissue. The microflora of the urinary bladder before the treatment and that of the urine from the kidney pelvis and the kidney tissue taken during the surgical operation was mainly ident

[Effect of tetracycline and oleandomycin on the indices of nonspecific resistance in aseptic inflammation under conditions of changes in the body's reactivity]. / Vliianie tetratsiklina i oleandomitsina na pokazateli nespetsificheskoi rezistentnosti pri aseptichekom vospalenii v usloviiakh izmenenii reaktivnosti organizma

The effect of tetracycline and oleandomycin on the complement titer, lysozyme content, serum bactericidal properties and presence of specific antibiotic antibodies in the blood serum was studied. The latter were shown with the Hoigné reaction under conditions of aseptic inflammation caused against the background of latent tetanus intoxication. It was shown that tetracycline and oleandomycin used in treatment of the animals with aseptic inflammation developed at the background of latent tatanus intoxication induced an increased in the complement titer, lysozyme content and bactericidal properties of the serum. Reduction of the above indices was observed by the 15th-20th day after discontinuation of the drug use. The increase in the factors of non-specific immunity under the effect of tetracycline and oleandomycin in the animals with aseptic inflammation caused against the background of latent tetanus intoxication was accompanied by appearance in the blood serum on non-specific antibodies revealed with the Hoigné reaction. Changed reactivity because of latent tetanus intoxication was accompanied by a delay in the formation of the non-specific antibodies in the blood serum. However, later the rate of their accumulation became higher and as a result the maximum titers of the antibodies were 2-3 times higher than those in the control animals.

Quantitative and qualitative determinations of the combined effect of tetracycline and oleandomycin. II. In vivo effect.

The combination effect of tetracycline (TC) and oleandomycin (OM) on acute infection of mice with four strains of Staphylococcus aureus including TC or OM resistant ones was examined by the quantitative determination of protective potencies of single and combined drugs. The grade of synergism was expressed by the synergistic ratio (SR), a ratio of experimentally determined potency of the combined drug over a hypothetical potency in which additive effect of the both drugs is assumed. With 3 out of the 4 strains of S. aureus synergism between TC and OM or triacetyloleandomycin (TAO) was demonstrated by the determination of the 50% effective dose and by statistical examination of the SR. The grade of synergistic protection by these drugs varied with the strains infected and it did not depend upon the sensitivity to antibiotics or grade of synergism in vitro. There was no synergistic enhancement of acute toxic action in the combined administration of TC and OM to mice.

[Effect of repeated cycles of tetraolean and oleandomycin administration on the indices of nonspecific resistence of the body in experimental staphylococcal sepsis]. / Vliianie povtornykh tsiklov vvedeniia tetraoleana, oleandomitsina na pokazateli nespetsificheskoi rezistentnosti organizma pri éksperimental'nom stafilokokkovom spesise

The effect of repeated cycles of tetracycline and oleandomycin administration on the complement titer, content of lysozyme and bactericidal properties of the serum in rabbits with experimental staphylococcal sepsis was studied. It was shown that the septic process induced by intravenous inoculation of staphylococci was accompanied by stimulation of the host nonspecific resistance. However, repeated inoculations of the animals resulted in exhaustion of the host protective forces and decreased non-specific resistance. The use of tetracycline in experimental staphylococcal sepsis was accompanied by an increase in the complement titer, lysozyme content and bactericidal properties of the serum after both the 1st and 2nd cycles of the drug administration. The use of oleaudomycin induced an increase in the contents of the complement, lysozyme and bactericidal properties of the serum at the background of staphylococcal sepsis only after the 1st cycle. The repeated cycle of oleandomycin administration was accompanied by a decrease in the above indices. Such conditions should be taken into account in choosing the antibiotic for treatment of septic cases especially when repeated cycles of the drug administration are used.